SPECIAL EDITION
2017
Medical Writing: The Backbone of Clinical Development
Medical
writing
the backbone of clinical development
Special Edition 2017
Leading the
transformation of R&D
www.synchrogenix.com
Medical Writing: The Backbone of Clinical Development
Publisher’s Introduction
Welcome to our special edition of International Clinical Trials, specifically created
to address the important topic of medical writing.
ICT, in partnership with Trilogy Writing & Consulting, have gathered medical
writing experts from around the world to help create a definitive guide to
medical documentation and the various challenges of developing it. The
carefully selected and esteemed contributors are thought leaders from across
the pharmaceutical and medical writing sector. Their articles raise much-needed
awareness of what is required and how best to go about producing accurate,
well-written documentation.
Whether you already are or intend to become a medical writer – or if you simply
need your medicinal product or clinical trial documented – we hope that you will
find valuable advice and practical tips in these pages, and wish you to keep it as a
handy reference.
We would like to thank Julia Forjanic Klapproth, a former President of the
European Medical Writers Association and a Senior Partner at Trilogy Writing
& Consulting, for her contribution as Chief Editor. Trilogy has played a crucial role in suggesting,
sponsoring, coordinating and editing this special edition. By doing so, they have once again confirmed
their deserved reputation as a leader in this industry.
Nick Matthews
International Clinical Trials
International
clinical trials
Chief Editor
Julia Forjanic Klapproth
Front Cover
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February 2017
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Medical Writing: The Backbone of Clinical Development
Foreword
By Janet Woodcock, M.D., Director of the Center
for Drug Evaluation and Research at the FDA
The health of Americans is the first priority of the FDA’s
Center for Drug Evaluation and Research (CDER). CDER
protects and promotes health by ensuring that human
drugs are effective and adequately safe, and that they meet
established quality standards. Excellent communication is
critical to both developing and properly utilising drugs.
Good medical writing and careful documentation factor
into each stage of the drug evaluation and review processes
– from the first phases of clinical research, through the
application and review process, and during the postapproval monitoring of marketed drugs. Through effective
communication of drug risks and benefits, we provide
healthcare professionals and patients with the information
they need to use medications safely and avoid medical
errors. All of these efforts require excellent medical writing and consistent documentation. We collaborate with many
stakeholders to make sure that the most reliable clinical, scientific and regulatory information is disseminated.
In this special edition of International Clinical Trials magazine, leaders in the field tell us about the importance of good
medical writing in a complex regulatory environment; how to write for different audiences and publications; and critical
tools, tips and tricks of the trade. They also share ways to overcome challenges and avoid common pitfalls, among other
key topics. We welcome their contributions and guidance in this effort.
Janet Woodcock, M.D.
Director of the Center for Drug Evaluation
and Research at the FDA
4
Medical Writing: The Backbone of Clinical Development
Foreword
By Melanie Carr, Head of Stakeholders and
Communication Division at the EMA
Medicines and knowledge are two principal outputs of
pharmaceutical endeavours. The twin yields – one tangible
and the other more abstract – have to work hand-in-hand
to maximise health benefits. Huge effort goes into making
medicines fit for use, being subjected to rigorous standards
for demonstrable quality and that all-important positive
balance between their benefits and risks. The European
Medicines Agency welcomes the attention now being
directed at that other crucial component of effective
healthcare and decision-making: the presentation and
dissemination of knowledge.
Knowledge is vital at every stage of a medicine’s lifecycle – from that first glint in the scientist’s eye at their origin, to the
delivery of a medicine to patients with detailed instructions on their safe use. And at each stage, this knowledge is passed
on in writing. Clear, accessible and accurate writing underpins the dissemination of precious and cumulative knowledge.
Continual advances to improve a medicine must run alongside enhancements in composing the associated knowledge, so
that the scientific and clinical communities as well as the public at large fully benefit from it.
This special edition of International Clinical Trials magazine prompts reflection on what makes medical writing effective
and why it is so important. Coherent, logical and appealing documentation aids decision-making, while poor-quality
writing can hinder it and run the risk of drawing flawed conclusions. From the regulator’s perspective, better quality
documentation is likely to foster better and more timely evaluation. At the user’s end, well-written information means that
the patient receives the right medicine, at the right dose and with the right instructions on how to take the medicine.
The adoption of clear writing principles is becoming important for another emerging reason: the march towards open
and accessible information as pioneered in the EU region. Many reports and documents written to meet regulatory
requirements have so far not been open to the public gaze. But now, those compiling these documents will see how their
work will be accessible to academics, clinicians and the public. A medical writers’ expertise and professionalism will need
to be deployed more than ever to come up with documents of the highest quality, which demonstrate sound science and
good practice of the bodies behind these documents.
The principles of good medical writing are becoming embedded in the world of medicines regulation; enthusiasm
over good writing and the sharing of ideas across the whole pharmaceutical spectrum will benefit patients, the
health community and society at large. The experience and skills of the authors of this special edition encompass the
fundamentals of clear, concise and accurate writing.
Melanie Carr
Head of Stakeholders and Communication
Division at the European Medicines Agency
5
Medical Writing: The Backbone of Clinical Development
CONTENTS
3
Publisher’s Introduction
4
Foreword from the FDA
5
Foreword from the EMA
8
Index of Advertisers
9
Foreword from Trilogy Writing & Consulting
10
The Need for, and Benefit of, Good Medical Writing
Karry Smith and Ann Winter-Vann at Whitsell Innovations, Inc. demonstrate the specific
abilities that professional medical writers bring to projects and how this expertise benefits
documents as well as clinical programmes.
14 What you Need and When – The Key Documents in the Drug Lifecycle
Julia Forjanic Klapproth at Trilogy Writing & Consulting provides a guide on how to organise
the high volume of documents required over the years it takes to bring a new drug to market.
19 Writing for Different Audiences
Medical writing must clearly communicate complex facts and concepts to a variety
of audiences; Kerry Walker and Nicola Evans from Insight Medical Writing explore how
best to hone the necessary skills for such a diverse task.
25 Clinical Study Protocols:
How to Write to Solve Problems Now and Avoid Big Ones in the Future
Kelley Kendle at Synchrogenix illustrates how clear identification of different responsibilities is
essential to maintain and improve the quality of protocol documents as well as prevent future mistakes.
28 Streamlining Clinical Study Protocols and Reports
Regulating the presentation of clinical study protocols and reports makes for more
comprehensive dissemination. Sam Hamilton at Sam Hamilton Medical Writing Services
and Julia Forjanic Klapproth at Trilogy Writing & Consulting discuss recent pharma initiatives
created to achieve easier understanding of complex documents.
32 The Challenge of CTD Submissions and Responding
to Questions from the Authorities
The Common Technical Document is required to achieve regulatory approval of medicinal products.
However, it presents an array of challenges and complexities, which Douglas Fiebig
at Trilogy Writing & Consulting advises how best to avoid and manage.
37 Getting Clinical Research Results Published
Clinical research aims to provide doctors with a thorough understanding of treatment options
and to improve medical practice overall. Phillip S Leventhal at 4Clinics and Stephen Gilliver at TFS
outline the importance of organisation and preparation in achieving this goal.
6
l
February 2017
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ICT
Medical
Contents
Writing: The Backbone of Clinical Development
44 Medical Publication Managers:
Are Your Publications Future-Proof and Audit-Proof?
Medical publication managers face the challenge of communicating the results of clinical research
to their audience in the most comprehensive manner possible. Discover the tools, techniques
and technology needed to help achieve accurate and credible documents as presented
by Professor Karen L Woolley and Dr Mark J Woolley at Envision Pharma Group.
50 The Pharmacovigilance Medical Writer:
Medical Writer, Project Manager, Regulatory Expert
A critical element of drug development and marketing is pharmacovigilance. Sven Schirp at
Boehringer Ingelheim and Lisa Chamberlain James at Trilogy Writing & Consulting take us through
how the evaluation and monitoring of patient safety and a product’s benefit/risk profile is a highly
regulated global task, which is required continuously throughout a medicine’s lifecycle.
54 Tips and Tricks for Medical Writers:
How to Produce High-Quality Regulatory Documents
Helen Baldwin at Scinopsis provides useful advice for medical and scientific authors through a
collection of rules and suggestions compiled over almost twenty years of professional experience.
59 Improving Statistical Reporting in Medical Journals
Medical writers must understand and accurately present the statistics that they cite.
Tom Lang of Tom Lang Communications and Training International shares an insight into the most
commonly used statistical parameters and tests and explains how to avoid some typical hazards.
63 Clinical Trial Disclosure and Transparency:
Ongoing Developments on the Need to Disclose Clinical Data
Kathy B Thomas focuses on the disclosure requirements of the EU and US, two leading clinical trial
and drug development regions, and their ramifications on sponsors and marketing authority holders.
71 Medical Writing for Submission to Asia-Pacific Regulatory Authorities
The team at PAREXEL concentrate on the growing need for quality medical writing services in
the Asia-Pacific region, as authors are needed to help teams navigate the different and numerous
regulations during document preparation.
78 Managing or Outsourcing your Medical Writing
Michael John Mihm at Astellas Pharma and Cortney Chertova at Randstad Life Sciences break
down best practices and successful strategies for managing or outsourcing medical writing
deliverables within a complex medical environment.
Index of Advertisers
Insight Medical Writing7
International Clinical TrialsIBC
Scinopsis57
SynchrogenixIFC
Trilogy Writing & ConsultingOBC
8
Medical Writing: The Backbone of Clinical Development
Foreword
By Julia Forjanic Klapproth, Senior Partner
at Trilogy Writing & Consulting
Dear Reader,
If you are reading this special edition on medical writing, it is very
likely that you are at least one of the following: someone interested in
becoming a medical writer, someone who is already a medical writer
or someone who has worked – or intends to work – with a medical
writer in the future. The idea for this special edition is to provide you
with useful information, regardless of which group you belong to.
I had the good fortune of discovering medical writing some 20 years
ago and it was love at first sight. It is a career that challenges one
intellectually, but also pulls on numerous facets of training gained
at university. In addition, when a good medical writer is in full swing,
they pull a team together and push them to achieve documents that truly help expedite drug approval, which is professionally
gratifying. Medical writers are people managers, idea miners, mediators, communicators and document wizards. Their
experience gives teams a measure of confidence when things get stressful, and helps keep them focused on pulling the right
information together and communicating what is needed for a particular document’s purpose.
Anyone who has worked with a good medical writer knows the value they bring to a writing team, yet many people in the
pharmaceutical industry still do not understand their role. The biggest and most common misunderstanding is that ‘anyone
can write’, meaning that a medical writer does not need any special training – or any training at all. As a result, numerous
people are employed as medical writers who, sadly, know nothing about the documents they are working on and do not have
the skillset to advise their teams on the directions to be taken. Teams who have worked with these untrained medical writers
also know how this can hinder the process. Expecting an inexperienced medical writer to work miracles with a document is
like expecting an inexperienced surgeon to work miracles with their surgery. Excellence comes from practice and training,
and it is worth making the effort to find a professional to do the job.
That is why it is important to evangelise the industry about the value and importance of high-end medical writing. This issue
of Medical Writing: The Backbone of Clinical Development brings together authors who are industry thought leaders in the
world of medical writing. With articles ranging from the basics to the specific, the goal is to raise general awareness about the
importance of producing well-written regulatory documentation. The articles explore how to overcome and avoid hurdles that
are reducing efficiencies when preparing these documents, and make clear the benefits of using experienced professionals.
In my ideal world, authoring teams of the future will comprise well-trained experts who bring their experience in their
respective domains; weaving the input from the clinical perspective together with that from statistics, pharmacovigilance,
regulatory and medical writing. In this world, teams will be able to better communicate throughout the lifecycle of a product,
ensuring that investigators and patients properly understand what needs to happen during clinical studies. Companies will
consequently obtain more consistent and robust data from those studies, and agencies will better understand the implications
of medicinal benefits and risks for the products they are required to assess. Ultimately, clear and effective documentation can
streamline the whole process of drug development, which would enable us to get new medicines and therapies to patients
who need them sooner and with less cost. Now that is a goal worth striving for.
Julia Forjanic Klapproth
Senior Partner at Trilogy Writing & Consulting
February 2017
l
9
Medical Writing: The Backbone of Clinical Development
The Need for, and Benefit
of, Good Medical Writing
The job of a medical writer involves authoring and editing a wide range of
documents that reach a variety of audiences. The main concern of the medical
writer is the clear communication of scientific information, which inevitably
involves specific tailoring of that document for the target audience. This task
necessarily requires a special skill set, which allows the medical writer to craft
this message. In this article, we introduce the skills that a professional medical
writer brings to a project and the ways that this expertise can benefit a document
and, more broadly, a clinical programme. We also discuss how other team
members can best assist a medical writer to produce high-quality documents.
Communicating Science
Science, admittedly, can be difficult to read and to understand.
At best, poorly written information confuses the reader; at
worst, it leaves its audience misinformed. According to the
1990 article by Gopen and Swan, the goal of all text is that
the “majority of the reading audience accurately perceives
what the author had in mind” (1). Simply stated, medical
writers write about medicine and health. Whether they author
publications, develop educational materials, or compile an
entire regulatory submission, medical writers are responsible
for clearly communicating complex scientific information.
What Is Medical Writing?
Medical writers are professionals with a broad expertise
in communication, who are skilled at presenting complex
information in a manner that is clear, logical, and attuned
to the needs of a particular audience. Medical writers
often have formal training in science, which provides a
solid foundation for gathering and evaluating medical
information. Professional medical writers contribute much
more, however. They understand ethical standards and
contribute a wide range of skills in project planning and
management. Altogether, the skills of a medical writer
contribute to improving each document they write and helping
each team they support. The broadly defined skills we present
in this article support the contributions illustrated in Figure 1.
By Karry Smith and
Ann Winter-Vann
at Whitsell
Innovations, Inc.
of words and phrases within a sentence can drastically alter
the perceived message (1). At a less granular level, a medical
writer weaves sentences together into paragraphs that form
the body of a document. The manner in which sentences are
arranged leads us to the next skill – organisation.
Organisation
The skill of organisation overlaps, in part, with grammar
and writing. Medical writers use organisational principles
(with the reader in mind) to construct sentences that convey
accurate information. On a less granular scale, organisational
principles govern the construction of paragraphs and the flow
of information within a document. For example, in scientific
publications, background information must be presented
and organised in such a manner that it leads seamlessly to
the research question at hand. In educational documents,
introductory information must sufficiently prepare the reader
to understand the subsequent information. The ability of a
medical writer to organise information ties in closely with
the ability to collect and critically review data.
Gathering and Analysis of Information
Grammar and Writing Skills:
The Foundation of Medical Writing
Medical writers are information managers. They must both
gather and analyse information at every step in the writing
process, before eventually determining which pieces of
information are incorporated into the final document.
Gathering information can involve research in the form
of literature reviews, or collating information from team
members, including statistical outputs.
At the simplest level, word choice can have a critical effect
on how well a message is communicated. Words that are
inaccurate or unfamiliar to those outside the field can obscure
the message and discourage the reader. The rules of grammar
govern the construction of sentences and dictate how words,
phrases, and clauses are combined; a failure to follow the rules
will distract or confuse the reader. More subtly, the location
Analysis involves breaking information down into its
constituent elements and using this as a basis for discussion,
interpretation, or examination of relationships. Analytical
writing, therefore, involves describing these ideas with the
written word. Medical writers comb through the statistical
outputs from a clinical study to identify relationships between
adverse events, medical history, and laboratory toxicities;
10
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February 2017
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Figure 1: Skills and areas of expertise of medical writers
compare and contrast the results of different treatment
groups; and describe key information from the tables, listings,
and figures. They carefully determine which information
supports and accurately conveys the study data. Not every
table or figure will find its way into a final clinical study report;
the sheer volume of the statistical outputs would bury critical
information in a pile of less informative data. Writers must
review all of the available information and determine what
goes into the text to tell the story. In order to accomplish this,
writers must have a solid understanding of statistics, which
allows them to curate and present the data appropriately.
In educational writing, analytical writing skills allow
medical writers to determine the organisation and flow
of information so that it makes logical sense. This includes
drawing comparisons and analogies between ideas to assist
the reader in understanding key points. When information
has been gathered, analysed, and curated, the next step
is to determine how to present the data.
Data Presentation
The order and manner in which data are presented affect
the ease with which a reader comprehends this information.
Gopen and Swan use the example of reversing the order
of columns in a table to drive this point home: the reader
can more easily interpret information when it is presented
11
in a format that the reader anticipates or is used to seeing
(1). Many times, information is better presented in a figure
than in text. Franzblau and Chung list three advantages that
graphs have over text (2):
• They portray complex information and comparisons
in a way that is easier to interpret and understand;
• They reduce reading time by summarising and
highlighting key findings; and
• They reduce the overall word count
The medical writer is often responsible for pulling out
important figures or tables from datasets that contain
hundreds of figures and tables. Once incorporated into
the document, the medical writer must then highlight the
key data in text.
When authoring publications, medical writers frequently
help design figures. A classic reference by Edward Tufte
outlines how good graphs communicate data – with
clarity, precision, and accuracy (3). If a figure is ambiguous,
confusing, or misleading, the medical writer will
suggest revisions.
For educational documents, medical writers create
flowcharts, choose which text to convert into short, bulleted
points, and pull in images to drive home key points to the
audience. The ability to clearly present data is important
in making sure the information can be understood by
the target audience.
Tailoring Text to the Target Audience
Different audiences have different needs for background
information, word use, sentence structure, and information.
Proper grammar, word choice, organisation, and
presentation all contribute to making a document clear,
simple, and easy to understand. We must ask ourselves:
“What message should the audience take home when they
are done reading our document or presentation, and how
can we help them reach that conclusion?” Using the example
of an educational document detailing the discovery of a
new drug, a research scientist may be most interested in
the mechanism of action, whereas a doctor might be more
interested in efficacy, the side effect profile, and potential
drug-drug interactions. The lay audience will likely require
more background and simplified (or more generalised)
information than those who are experts in the field.
Reviewers at regulatory agencies would be most interested
in the safety and efficacy data.
Project Management
Whether authoring a regulatory document or drafting a
lay summary, medical writers are, first and foremost, skilled
at writing. However, their contributions to a document go
beyond grammar and data presentation, because their
12
responsibilities include more than just writing. Medical
writers are often project managers: creating timelines,
meeting deadlines, and managing input coming from
multiple sources. Because of their organisational skills,
medical writers are able to keep multiple documents moving
forward, make accurate edits and updates, and ensure that
all team members are heard.
In its Guide to the Project Management Body of Knowledge,
the Project Management Institute describes a framework
for project management (4). This framework includes
five processes that have been defined and applied to
publications writing by Auti et al but are equally applicable
to the regulatory and educational writing arenas: initiation,
planning, execution, monitoring and control, and closure (5).
In regulatory writing, initiation might involve developing
a scope of work and hosting a kick-off meeting. The next
process, planning, begins by assigning project roles, gathering
a core team, and creating an agreed-upon timeline for the
project. Execution involves many standard procedures –
drafting text, managing review cycles, resolving comments,
gathering necessary information from team members, and
preparing a final draft for team review. Monitoring and
control of the project involves defining risks that could impact
timelines and creating solutions to these problems. The fifth
and final process is closure, which involves delivering the final
Dos and Don’ts of Medical Writing
Do:
• Let the writer know if you will be on vacation or
unavailable for a period of time
• Provide text as requested (by the deadline)
• Keep the writer informed of any changes to the
programme that might affect the document
• Use the agreed upon review system
• Provide actionable comments
• Provide specific references and source documents
• Meet deadlines for review of the document
• Consolidate comments by functional area
(eg statistics, safety, regulatory)
• Decide upon preferred styles and wording early in the
process. This step is particularly important for large
submissions so that the full set of submission documents
can be consistent in style and presentation
Don’t:
• Ignore questions or forget to respond to the medical writer
• Send multiple versions of a document to the entire team;
this can lead to version control issues
• Focus on minor wording issues and miss the “big picture”
• Get distracted by findings that do not pertain to the study
objectives and endpoints
• Skip comment review meetings
• Wait until the final draft to actually read the document
product, completing any final documentation required by
company standard operating procedures, and in some cases,
reviewing how the project went in order to further streamline
the activity the next time.
Review and Revision:
Creating the Final Document
We indicated in the introduction that the main concern of
the medical writer is the clear communication of scientific
information. The final form of this information is a document
that, after weeks, months, or even years of work, reaches its
intended audience. Each document passes through multiple
stages of review and revision. New data might become available
or a new advance in the field might affect the science that
supports the document. Because scientific fields evolve rapidly,
and because many individuals contribute, the review and
revision process ensures that the project is completed and that
all input is considered: all voices are heard. To accomplish this,
medical writers work with team members to resolve conflicting
comments, revise the document, and keep record of changes
to the document over time. Because documents often change
in real time, soliciting resolution and a final approval from the
team are key steps in completing a document.
Technological Expertise
Medical writers are experts in the tools of document writing,
adept at using software such as Microsoft Word, Excel, and
PowerPoint, and Adobe Acrobat. Their expertise includes
an advanced knowledge of the powerful functions of these
programmes that make a document consistent in formatting
and style, navigable, and stable – even in documents that are
hundreds of pages long and include dozens of tables and figures.
These highly formatted, stable documents eliminate the need for
tedious and time-consuming revisions by the publisher.
Depth of Experience
Because writers work with many teams across different
therapeutic areas and different stages of clinical
development, they add depth and breadth of experience to
each project. Experienced medical writers understand how
various documents fit together throughout the lifecycle
of a clinical programme: well-written protocols allow the
collection of data to support the objectives and endpoints
of a study. Clinical study reports present those data with
a clear, consistent message that is then conveyed to the
public through posters, presentations, and publications.
The messages are combined across a clinical development
programme to support the eventual submission.
Getting the Greatest Benefit from Adding
a Medical Writer to Your Team
It should be evident by now that the medical writer is a
key contributor and coordinator of any regulatory writing,
publications, or educational writing team. The medical writer
necessarily interacts with all members of the team.
To get the most from this interaction, we recommend
some “Dos and Don’ts” that will assist the medical writer
in producing high-quality, on-time documents (see
previous page).
References
1. Gopen GD and Swan JA, The science of scientific writing,
American Scientist, 1990
2. Franzblau LE and Chung KC, Graphs, tables, and figures in scientific
publications: The good, the bad, and how not to be the latter, J Hand
Surg Am 37(3): pp591-596, 2012
3. Tufte ER, The visual display of quantitative information, Graphics Press, 2001
4. Project Management Institute, A guide to the project management
body of knowledge (PMBOK® Guide, Fifth Edition), Project Management
Institute, 2013
5. Auti P et al, Project management in medical publication writing:
A less explored avenue in pharmaceutical companies and clinical research
organisations, Medical Writing 25(1): pp36-44, 2016
About the authors
Karry Smith earned her Master of Public
Health degree in Epidemiology and her
PhD in Cell and Developmental Biology
from the University of Iowa. Following
two postdoctoral fellowships – one at
the University of Iowa Carver College
of Medicine (Biochemistry) and a second at Mayo Clinic
(Physiology and Biomedical Engineering) – Karry joined
Whitsell Innovations, Inc., as a Medical Writer. She has
experience in both regulatory writing and science education,
and is a current member of the American Medical Writers
Association (AMWA), the Regulatory Affairs Professionals
Society, and the Drug Information Association.
Email: [email protected]
Ann Winter-Vann is a Lead Clinical
Regulatory Writer and Manager with
Whitsell Innovations, Inc. In addition
to writing a wide variety of regulatory
documents, she provides client
consultations and training sessions for
medical writers. Ann earned her PhD in
Molecular Cancer Biology from Duke University, where she
was a predoctoral fellow of the Howard Hughes Medical
Institute. Ann joined the company after completing a
postdoctoral research fellowship at UNC-Chapel Hill. She
is a past president of the Carolinas Chapter of the AMWA
and the current AMWA Administrator of Publications and
member of the Executive Committee.
Email: [email protected]
13
Medical Writing: The Backbone of Clinical Development
What you Need and When –
The Key Documents in the
Drug Lifecycle
Clinical development is a complex and expensive undertaking, involving
many years of research that culminate with clinical trials, the objectives and
results of which all have to be documented. This article provides a pathfinder
to which documents need to be prepared, when they are needed, and who
they need to be submitted to.
By Julia Forjanic
Klapproth at Trilogy
Writing & Consulting
Throughout the lifecycle of a medicine, documents are
the key means for designing, conducting and reporting
trials in human subjects, as well as for monitoring the
quality manufacturing, packaging, labelling, safe usage and
performance of drugs once on the market (see Figure 1).
The ICH guidelines – particularly ICH E6 – provide a unified
standard for the EU, Japan and the US to facilitate the
mutual acceptance of clinical data by regulators within these
jurisdictions, laying out the essential documents required
to proceed through the clinical lifecycle and meet
regulatory requirements (1).
Documents Required Before
the Start of a Clinical Trial
Many of the documents needed are relatively straightforward
forms that need to be completed with the appropriate
information. Some, however, are more complex and require
the efforts of multifunctional teams to pull together the
information needed. In particular, experienced medical
writers bring value to the process of weaving it all together
in a way that effectively communicates the intentions and
Prior to testing any new medicine or therapy on human
subjects in a clinical trial, the drug developers must apply
for permission to run clinical studies by submitting an
Investigational New Drug (IND) application in the US or an
Investigational Medicinal Product Dossier (IMPD) in any of the
EU Member States (see Figure 1). For the initial human studies,
these applications summarise manufacturing information, all
objectives of each document. This article aims to provide an
overall summary of the documents that medical writers can,
and should be involved in, as expert communicators who can
ensure the documents are fit for purpose across the lifecycle
of clinical drug development, approval and marketing. It will
focus on the key documents required at each stage of the
drug lifecycle, describing their content, purpose, audience,
and deadlines for submission.
Marketing
Authorisation
Approval
(MAA)
Clinical Trial Cycle
Pharmacovigilance
(PV) Cycle
New
Medicine
Initial
Registration
Clinical
Development
Plan (CDP)
by means of an
Investigational New
Drug (IND)
application in the
US or Investigational
Medicinal Product
Dossier (IMPD) in the
European Union (EU)
pre-clinical phase
Clinical Study
Protocol (CSP)
Investigator's
Brochure (IB)
l
February 2017
Development
Safety Update
Report (DSUR)
Clinical Study
Report (CSR)
Assessment, definition of further trials, study of
specific population groups (eg requiring
paediatric investigation)
Submission for
Approval
Marketing
and Patient
Communication
requires preparation
and submission of
Common Technical
Document (CTD), Risk
Management Plan
(RMP) and any
necessary responses
to assessors
questions
including abstracts,
manuscripts, posters,
publications, patient
advice, health
professional
information. Also
possible: postmarketing trials
clinical development phase (drug trials in human subjects)
Figure 1: Documents in the drug lifecycle
14
Informed
Consent
Form (ICF)
Periodic
Safety Update
Report
(PSUR)
Risk
Management
Plan (RMP)
update
Ongoing continuous
monitoring of drug safety
and performance
drug marketing phase
EU documents
US documents
Nature and purpose
Investigational
Medicinal
Product Dossier
(IMPD)
Investigational
New Drug (IND)
Application
Investigator's
Brochure (IB)
Investigator's
Brochure (IB)
A compilation of all the relevant clinical and medicinal data of an investigational new drug or medicinal product,
as relevant when studying the medicine in human subjects
Clinical Study
Protocol (CSP)
Clinical Study
Protocol (CSP)
A document that lays out strict guidelines for the performance of a clinical trial. Based on the most current data
about the disease under treatment and the medicine being tested, the protocol lays out guidelines for diagnosis,
prognosis, handling of subjects, dosage of medicines and risk/benefit considerations, providing decision options
and their expected outcomes
Informed
Consent Form
(ICF)
Informed Consent
Form (ICF)
Paediatric
Investigation
Plan (PIP)
Pediatric Study
Plan (PSP)
An application for permission to use an investigational product in a clinical trial with human subjects.
A separate IND or IMPD is required for each product used in a trial (including placebo). These documents may
need updating for the approval of each new clinical trial, if the known information about an investigational
product changes significantly
A document to be signed by all subjects who are to take part in the clinical trial – to confirm that they understand
and accept the objectives, methods and risks involved
A development plan that is required if the investigational product is to be licensed for use in children. It describes
how clinical data will be obtained safely in clinical studies with children
Table 1: Documents needed to start a clinical trial
data available to date from animal studies including toxicity
data, the clinical study protocols (CSPs) for the planned clinical
studies and information about the investigators who will run
the studies. As the development programme proceeds, the IND
or the IMPD must be updated for each new study, adding new
data from animal and human research available at the time the
new study application is made.
There are a number of key documents that need to be written
to be able to run the clinical studies, as explained in detail in
ICH E6. The most important of the documents defined by ICH E6
are the CSPs, the informed consent forms (ICFs) and Investigator
Brochures (IBs) (see Table 1 and Figure 1). The purpose of
these is to:
• Lay out clearly the scientific information available
about the product (in the IB)
• Explain the rationale for performing each study (in the CSP)
• Provide a detailed investigational plan and describe the
analyses to be made to achieve the objectives of a study
(in the CSP)
• Explain the details and intention of the trial in lay language
for subjects participating in the trial (in the ICF)
These documents are often complex collections of thoughts
that need to build on each other to tell a clear story of what
the trial hopes to achieve and how. The coordination and
writing of these documents warrants the use of an experienced
writer who knows how to pull together input from the many
stakeholders involved in the authoring process, and to make
sure their ideas are consolidated into a consistent reflection
of the planned studies.
It should be kept in mind that the complexity of these
documents tends to increase as the development
programme proceeds. Clinical development begins with
Phase 1 clinical trials that are conducted with just a few
human subjects to assess the safety and pharmacokinetics
of the medicine. Phase 2 clinical trials follow, in which initial
efficacy assessments are made in subjects with the target
disease and dose finding studies are made to identify the
optimal dosage of the medicine. Ultimately, large-scale
Phase 3 trials are performed to unequivocally demonstrate
the efficacy of the product at the planned dosage and to
better understand the safety profile.
As a result, the CSPs of Phase 1 and simple Phase 2 studies
often have few assessments, are small and less complex, and
can be written quickly with only a few drafts. In contrast,
a complicated Phase 2 or 3 CSP that has several objectives
(eg efficacy, safety, pharmacokinetics and quality of life),
assessment of multiple dose groups or treatment regimens,
and perhaps includes sub-studies, may take months of
discussion and consideration to develop. This means there will
usually be numerous drafts and multiple rounds of revision as
various stakeholders are asked to contribute their opinions on
the design and activities to be performed.
Likewise, an IB needed in later stages of clinical development
is a much more difficult document to write. The intention of
the IB is to inform investigators who will be running studies
about all available information on the PK profile, efficacy
and safety of the drug being tested. By Phase 3, there is a
wealth of clinical data available that needs to be condensed
and consolidated into a brochure that is still easy and quick
for the investigator to read. This takes much more skill and
experience as a writer than the early editions of an IB. Thus,
the demands on the team as a whole – but particularly on
the medical writer – increase considerably with the rising
complexity of documents in later stages of development. It is,
therefore, important to ensure that the experience and skill of
the medical writer is carefully matched to the demands of the
documents in these different phases.
For investigational products that will be licensed for use in
children, it is necessary to write a development plan focused
specifically on the studies to be performed in children. This
Paediatric Investigation Plan (PIP) in the EU, or Pediatric
Study Plan (PSP) in the US, describes how clinical data will
be obtained in studies involving children to support the
15
Document
Nature and purpose
Development Safety
Update Report (DSUR)
A comprehensive annual review and evaluation of safety information relating to drugs under development, which must be
revised annually as necessary
Clinical Study Protocol
(CSP) amendment
Revisions to the original CSP that reflect changes in the design or investigational plan, eg due to practical problems in running
the study or unexpected outcomes
Investigator's Brochure
(IB) updates
Prior to the start of any new clinical trial, the IB must be updated with any data from prior studies; at a minimum, updates are
required at least annually to reflect any changed information
Pregnancy prevention
plan or programme (PPP)
Statistical Analysis Plan
(SAP)
A document laying out a set of interventions intended to reduce the likelihood of pregnancy during treatment with a medicinal
product with known or potential teratogenic effects
A detailed description of the statistical analyses to be performed on the data collected during the clinical trial, based on the
statistical analyses described in the CSP. This includes the rationale and references for why particular statistical methods are
appropriate for the planned analyses
Table 2: Documents to be authored during the conduct of clinical trials
authorisation of a medicine for them. These are not trivial
documents, as they must provide detailed background
information about what is known about the disease in
children and what treatment options are already available;
describe the measures to adapt the medicine's formulation to
make its use more acceptable in children (eg use of a liquid
formulation rather than large tablets); and address how the
studies will cover the needs of all age groups of children (from
birth to adolescence). Teams often underestimate the amount
of time they will need to discuss, develop and agree on the
content of their paediatric plans and it is important that
the writing timelines plan for sufficient time to develop the
document properly.
Documents Needed During the
Conduct of a Clinical Trial
Once the clinical trials are running, the writing activities are
far from over. Several documents need updating or writing
throughout the course of a clinical programme, and many of
these are written during the conduct of clinical trials
(see Table 2). There are often amendments to the CSPs, which
describe changes to the planned study or analyses, frequently
because the original study design proves to be impractical, and
the activities need to be adapted to make them more feasible
or to increase patient recruitment.
Pharmacovigilance data that are collected during the conduct of
a clinical development programme needed to be reported in a
cumulative, ongoing manner in the annual Development Safety
Update Report (DSUR). Updates to IBs need to be generated in
preparation for the start of upcoming studies. The final statistical
analyses of the trial data need to be defined in advance of looking
at the data, and these are described in the Statistical Analysis Plan
(SAP). It is important that clinical teams have all these documents
on their radar to plan for them accordingly. There is nothing
more frustrating than recognising a week before a new study
is meant to be submitted that an important document, such as
an updated IB, is not available. By mapping out the preparation
of all these documents relative to the ongoing clinical studies,
writing resources can be planned out well in advance and delays
in starting new studies can be avoided.
Documents Needed after Completion
or Termination of a Clinical Trial
Following completion of a trial, a comprehensive clinical
study report (CSR) must be written that provides a detailed
description of the results of the study, whether positive or
negative. In addition to describing the methodology of how the
study was run (including changes to the original plan according
to the CSP), all of the information collected during the study
needs to be reflected in this report. Again, depending on the
clinical phase of development, a CSR can be a relatively short
document (eg summarising a small Phase 1 pharmacokinetic
[PK] study) or immensely complex and long (eg for a Phase
3 study with numerous assessment parameters and in a
particularly complex therapeutic area). While the former may
only take a few weeks to write, the latter can take 6 months
or more for a team to craft and develop the storyline. Often
it is simply the sheer amount of data that everyone has to
wade through and digest that slows the process. However, it is
important to give teams the time to do this properly – taking
time to think ideas over and refine the messages through
Once the clinical trials are running, the writing activities
are far from over. Several documents need updating or writing
throughout the course of a clinical programme, and many of these
are written during the conduct of clinical trials
16
Document
Nature and purpose
Clinical Study Report
(CSR)
A mandatory report covering the objectives, conduct and outcomes of the clinical trial. Note: the EU has recently
defined a clinical trial report as a CSR pertaining to an interventional (rather than non-interventional) study
Clinical Trial Summary
A summary of a CSR, including a summary understandable to a layperson, to be uploaded onto a
publicly available clinical trial registry (eg www.clinicaltrials.gov in the US or www.clinicaltrialsregister.eu in the EU)
Table 3: Documents needed after clinical trials have ended
a couple of iterations – since well-written text and more
complicated thought processes take time to hone.
It is now obligatory to post a summary of the clinical trial results
for studies performed in the US or EU on online databases for
access by the general public. This summary must be submitted
within 1 year of completion of the trial (ie last patient last visit,
as described in FDAAA 801 Requirements in the US, and the
detailed guidance for the request for authorisation of a clinical
trial on a medicinal product for human use to the competent
authorities in the EU (2,3)). From the writing perspective, it is
important to know that the reports posted on these public
databases may not include any information that allows
identification of any subject in a study, as outlined in the EMA
policy 0070 (4). Hence, the medical writer should help their
authoring teams understand potential implications of the
information included in a CSR to avoid unnecessarily large
efforts for redaction when creating these summaries
(see page 63 for more detail about the EMA policy 0070 and its
implications for public disclosure).
Documents Needed to Apply for
Marketing Authorisation
After completion of the clinical development programme,
the data collected need to be pulled together in a dossier
that will be submitted as an application for marketing
authorisation. These dossiers consist of summary documents
written according to the guidelines of the common technical
document (CTD). The clinical part of the CTD dossier
comprises Module 2.5 (the clinical overview) and Module
2.7 (summaries of clinical pharmacology, biopharmaceutics,
clinical efficacy and clinical safety) (see Table 4).
Writing these dossiers is the pinnacle of the medical writing
challenge to synthesise numerous ideas and data points into
a cohesive description of what is known about the medicinal
product. The documents need to be written so that the
regulatory reviewers can quickly understand what data are
available from the clinical programme, and what these tell
us about the PK profile, efficacy and safety of the drug, and
the nature of its relative benefits and risks. Depending on the
complexity of the product and the indication for which it is to be
used, writing Modules 2.5 and 2.7 can take anywhere from 6-12
months (the writing and coordination of CTDs is discussed in
more detail on page 32).
As part of the application dossier, the sponsor must plan for
how any potential risk associated with use of the medication
will be monitored for and minimised. This plan is laid out in the
Risk Evaluation and Mitigation Strategies (REMS) document in
the US (which is only required on request of the FDA) or the
Risk Management Plan (RMP) in the EU (which is mandatory).
As the name suggests, the document draws on all previous
experience and reports of the drug to assess the main risks
and to consider what would be appropriate precautions for
ensuring appropriate monitoring and mitigation of those risks.
The RMP also requires a summary for the layperson – ensuring
that patients have full access to information about the risks of
treatments they are being prescribed.
Documents Needed during Marketing (Phase 4)
In order to make health authorities, physicians, health
practitioners and patients aware of a new drug – including
its potential benefits and risks – the data gathered during
the clinical studies are published in the form of posters,
abstracts, manuscripts, patient information sheets and
informative websites. There are very strict compliance rules
around how marketing may be conducted, and what claims
may be made in these documents.
In addition, specific material, including that derived from
specially designed post-marketing (Phase 4) clinical studies,
may be collected for the purpose of Health Technology
Assessment (HTA) to gain specific knowledge about particular
safety aspects of the drug, or to understand its performance
in certain patient populations. HTA is the process by which
national health authorities aim to assess the affordability of new
drugs – comparing their benefits against their costs and that of
alternative treatments.
Once a product is on the market, all records of reported safety
events must be collated and assessed on an ongoing basis. This
is done in the form of the periodic benefit-risk evaluation report
(PBRER, previously the Periodic Safety Update Report, PSUR),
as described by ICH E2C (R2) (5). The purpose of the PBRER is to
harmonise the worldwide reporting of safety experience of a
medicinal product after approval. Since the timing of when these
reports must be submitted each year is regulated, preparation of
these documents is often done under extreme time constraints
between obtaining the data summaries for a reporting period
and producing the final report. Since much of the data being
assessed is in a similar format each time, it is possible to
standardise the production and presentation of these data, which
can go a long way to streamlining the writing process by allowing
teams to focus their efforts on looking for safety signals, rather
than agreeing on how to present the information.
17
Document
Module 2.5: Clinical Overview
Module 2.7.1: Summary of
Biopharmaceutic Studies and Associated
Bioanalytical Methods
Module 2.7.2: Summary of Clinical
Pharmacology Studies
Module 2.7.3: Summary of Clinical Efficacy
Module 2.7.4: Summary of Clinical Safety
Risk Evaluation and Mitigation Strategies
(REMS) in the US or Risk Management Plan
(RMP) in the EU
Nature and purpose
A short (up to 40 pages) critical assessment of the clinical data culminating
and a benefit/risk assessment of the product
A summary of the formulation development process, the in vitro and in vivo dosage form performance,
and the general approach and rationale used in developing the bioavailability (BA), comparative BA,
bioequivalence and in vitro dissolution profile database
A summary of the clinical pharmacology studies that evaluate human PK, pharmacodynamics and in vitro
studies performed with human cells, tissues, or related materials (hereinafter referred to as human biomaterials)
that are pertinent to PK processes
A summary of the programme of controlled studies and other pertinent studies in the application that
evaluated efficacy specific to the indication(s) sought
A summary of data relevant to safety in the intended patient population, integrating the results of individual
CSRs as well as other relevant reports, such as the integrated analyses of safety that are routinely submitted in
some regions. The aim is to clearly describe the safety profile of the product
To succinctly describe how the risks of a product will be prevented or minimised in patients, provide plans
for studies and other activities to gain more knowledge about the safety and efficacy of the medicine,
identify risk factors for developing adverse reactions, and to explain how the effectiveness of risk
minimisation activities will be measured
Table 4: Key clinical documents prepared to apply for marketing authorisation
Summary
Throughout the clinical lifecycle of a medicinal product, a
myriad of documents are needed to effectively plan, run and
then assess and communicate the outcome of the clinical
studies performed. Many of these documents are complex
compilations of data and thoughts, and also function in
conjunction with other documents – meaning they all need
to tell a consistent story.
It is important to have experienced stakeholders on the
authoring teams, including a medical writer who has the
experience with the document types to know how to advise
teams on the needs of a particular document and to guide
authors through the review and revision process. Planning
well in advance and ensuring enough time is given to the
authoring teams to allow them to think about, discuss and
craft documents that accurately reflect what the data have to
say, will ensure that these documents are fit for purpose while
making the writing activities less arduous for
everyone involved.
References
1. Visit: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Efficacy/E6/E6_R2__Addendum_Step2.pdf
2. FDAAA 801 Requirements as described in Section 801 of the Food and
Drug Administration Amendments Act. A summary can be found at www.
clinicaltrials.gov/ct2/manage-recs/fdaaa
3. Official Journal of the European Union, Communication from the
Commission, Detailed guidance on the request to the competent
authorities for authorisation of a clinical trial on a medicinal product for
human use, the notification of substantial amendments and the declaration
of the end of the trial (CT-1) (2010/C82/01)
4. European Medicines Agency policy on publication of clinical data for
medcinal products for human use. Policy 0070 EMA/240810/2013. Visit:
www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/
It is important to have
experienced stakeholders
on the authoring teams,
including a medical writer
who has the experience
with the document types to
know how to advise teams
on the needs of a particular
document and to guide
authors through the review
and revision process
About the author
After receiving her PhD in Developmental
Neurobiology, Julia Forjanic Klapproth
started her career as a medical writer in
the regulatory group at Hoechst Marion
Roussel (later Sanofi) in 1997. Since
then, she has been president of the
European Medical Writers Association twice. In 2002, Julia
co-founded Trilogy Writing & Consulting Ltd, a company
that specialises in providing regulatory medical writing. In
addition to managing the company as Senior Partner, she
writes a wide array of clinical documents including study
protocols, study reports, and the clinical parts of CTD
submission dossiers.
WC500174796.pdf
5. ICH guideline E2C (R2) on periodic benefit-risk evaluation report (PBRER).
EMA/CHMP/ICH/544553/1998
18
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Writing for Different Audiences
Medical writing is a wide-ranging discipline catering for a variety of
audiences, from regulatory experts and healthcare professionals to the lay
public. All medical writing must clearly communicate often complex facts and
concepts, and this is underpinned by the fundamental principle of knowing
your audience.
By Kerry Walker and
Nicola Evans at Insight
Medical Writing
Introduction
Regulatory and Pharmaceutical Audience
As a discipline, medical writing encompasses everything
from the preparation of confidential clinical and regulatory
documentation to lay summaries. In all medical writing, facts
and concepts must be communicated in a clear, concise
fashion. However, information can only be effectively
communicated by use of language, style and content that is
appropriate to the target audience. No reader likes to be
faced with impenetrable wording. Equally the informed
reader will not appreciate over-simplistic text.
Preparing regulatory documentation provides a fascinating
challenge to the writer. While these documents are
primarily for assessment by regulatory authorities, they
represent the culmination of years of drug development on
behalf of the sponsor. This considerable investment in time
and cost is ultimately judged on the data and documents
submitted. Thus, the production of high-quality documents
is critical and can ensure smooth progress through
submission and beyond.
The importance of telling a story is often overlooked in
scientific writing; however, leading the reader through a
logical, structured argument is more effective than simply
listing facts. Good writing uses rhythm and pace to engage
the reader. Although judicious use of short sentences
can be effective, overuse can feel abrupt and disjointed.
Conversely, long, overcomplicated sentences can be difficult
to follow. Precision, as well as consistency in terminology and
presentation, is also crucial in helping the reader understand
key points and conclusions.
Writing for regulatory assessment is distinct from writing for
other audiences in that it involves the production of large
submission packages that provide comprehensive information
for in-depth review by regulatory authorities. While
established guidelines and templates ensure that documents
conform to predefined structures, the challenge is to craft an
effective presentation of large bodies of data, highlighting
benefits while maintaining transparency of potential risks and
limitations. It is critical that content is presented in a clear,
accurate and objective fashion. Effective cross-referencing
is also essential to facilitate both navigation across documents
and location of sources.
The target audience can be divided into three broad categories:
1. R
egulatory bodies and pharmaceutical experts
2. H
ealthcare professionals (eg doctors, nurses
and pharmacists)
3. The lay public not otherwise involved in the pharmaceutical
or healthcare professions (eg patients)
While there are specific considerations and techniques that
distinguish writing for each audience, many areas overlap
(see Figures 1 and 2). For all audiences, however, the key to
successful and appropriate writing is to be CLEAR (see
table below). This article will discuss the techniques and
requirements to effectively write for each audience.
Linguistically, regulatory writing adopts a formal, scientific
style, outlining the purpose and objectives of each document.
Text, tables and figures should facilitate effective review by
regulators. Appropriate scientific and regulatory terminology
that is routinely accepted and/or standard practice should
be used. A well-recognised example is the use of the Medical
Dictionary for Regulatory Activities (MedDRA) instead of
colloquial terms to describe adverse events.
Strategic document planning should commence early in
the development process while always focusing on the
final regulatory submission. Involvement of an experienced
Concise, with an appropriate level of detail
Logical, enabling the reader to follow the facts and arguments presented
Evidence-based, for scientific integrity
Accurate, avoiding data or text errors
Readable, by the target audience
Key attributes of successful writing
February 2017
l
19
Regulatory/pharmaceutical
• Benefit-risk evaluation
• Facilitate review
• Strategic development
• Templates, guidelines
and conventions
• Good background
Concise
knowledge
Logical
Evidence-based
Accurate
Readable
• Direct support of claims
•M
arket/competitor
positioning
•R
aising awareness of
product and indication
• Design and layout
• Word limitation
Healthcare professionals
•T
ransparency
and redaction
• Focus on individuals
•M
inimal background
knowledge
• L ow literacy level/
non-native speakers
Layperson
Figure 1: Writing considerations for different audiences
medical writing team can greatly enhance this process.
For example, a well-designed and written protocol not
only assists the running of the study and reduces the
need for amendments, but also facilitates writing of the
clinical study report (CSR) and ultimately the submission
documents. Each document in the dossier should be
written using a consistent style and approach to ultimately
feed into the regulatory package.
Medical Writer’s Associations together with other contributors.
This initiative resulted in development of the Clarity and
Openness in Reporting: E3-based (CORE) Reference user
manual, which incorporates ICH E3, subsequent clarifications
published in 2012, and suggestions to facilitate public
disclosure of clinical trial results (3). An article specifically
discussing this initiative is provided elsewhere within this
supplement (see page 28).
Guidance
International guidelines, which suggest appropriate content
and structure for regulatory documents, are an essential
resource for every medical writer. Since submissions may be
made to one of numerous competent authorities, awareness
of national and international guidelines is vital. For example,
the EU-specific Risk Management Plan (RMP) is defined in
guidance from the EMA (1), and a template for the Canadian
Product Monograph is provided by Health Canada (2).
For all dossiers submitted to the EMA since 1 January
2015, submission documents including the CSR, Clinical
Summary, and Clinical Overview will serve two purposes
(4). While still primarily intended for regulatory assessment,
they are now to be made publicly available following
redaction of information that is either commercially
sensitive or might identify individual patients. Content for
redaction is agreed in advance with the EMA; however, the
medical writer will play an important role in the process.
As anticipated in the CORE Reference, the challenge for
medical writers will be to produce a ‘primary use’ CSR
for regulatory review that pre-empts the need for later
redaction by retaining data meaning and context, while
anonymising patient information. Such a proactive
approach will minimise the efforts needed to produce the
‘secondary use’ CSR intended for public disclosure, thereby
improving both efficiency and transparency.
While guidelines are not intended to be absolute
requirements, their detailed nature means that, in practice,
document templates tend not to deviate significantly from
the format provided. Associated clarifications and work aids
may also assist with interpretation of the original guidance.
A notable example is the CSR guidance, ICH E3, which has
recently been evaluated by the European and American
20
Style
Consistency of terminology and style
Regulatory/pharmaceutical
Healthcare professionals
Examples: CSRs,
submission documents
Examples: information
sheets, marketing tools
• Formal style
• Comprehensive,
objective data
presentation
•U
se of scientific terminology
and standard regulatory terms
• Variable style
• Distilling information to key
points and messages
• Use of scientific terminology
Lay public
Examples: informed
consent, lay summaries
• Informal style
• Distilling information to key
points and messages
• Careful/limited use of
scientific terms
• Simple language and
sentence structure
Figure 2: Writing style for different audiences
Healthcare Professional Audience
Effective communication between the pharmaceutical
industry and healthcare professionals provides prescribers
with the most recent, accurate information, and ensures that
medicines are used safely and appropriately for maximum
patient benefit. Successful product approval is of limited
benefit if healthcare professionals remain unaware or
unconvinced of its potential utility. While the best writing
raises awareness and knowledge of new treatments, poor
quality writing can mean that key messages are lost.
Similar to regulatory documentation, writing for healthcare
professionals targets an ‘expert’ audience who will critically
assess the information provided. Technical language is
appropriate and the emphasis should be on accuracy. However,
in contrast to regulatory documentation, information presented
to healthcare professionals is necessarily abbreviated. Although
publications in scientific journals must comprehensively discuss
specific studies or data, information is ultimately constrained
by word limits and can rarely be presented in the context of
the overall clinical development programme. Direct marketing
materials for healthcare professionals present an even greater
challenge, as they must effectively convey key data to an
audience that typically devotes a relatively small amount of
time to communications from pharmaceutical companies.
Writing for healthcare professionals therefore requires key data
to be communicated concisely to a time constrained audience,
while providing sufficient detail for adequate assessment.
Industry Codes of Practice
It is widely acknowledged that trust in the pharmaceutical
industry has declined in recent decades. Scepticism of
pharmaceutical companies is reflected among healthcare
professionals for a variety of reasons, including underreporting of negative results (5). When presented with trials
of hypothetical drugs, doctors downgraded the rigour of an
industry-funded clinical trial and had less confidence in the
results compared to a similar quality trial with no funding
disclosure or with support from the National Institutes of
Health (6). Restoring faith in communications to healthcare
professionals is central to rebuilding industry trust. To this
end, guidelines outlining good practice for healthcare
communications are available.
In the US, many major pharmaceutical companies are
signatories to the Pharmaceutical Research and Manufacturers
of America (PhRMA) Code on Interactions with Healthcare
Professionals (7). Central to the code is that promotional
materials should be accurate and not misleading, claims
should be substantiated, and information should both reflect
the risk-benefit balance of the product and be consistent
with other FDA requirements governing communications.
These principles are also reflected in the Association of the
Although publications in scientific journals must
comprehensively discuss specific studies or data, information is
ultimately constrained by word limits and can rarely be presented in
the context of the overall clinical development programme
21
British Pharmaceutical Industry (ABPI) Code of Practice,
which indicates that communication materials must be “…
appropriate, factual, fair and capable of substantiation and
that all other activities are appropriate and reasonable” (8).
The code also includes detailed criteria for the content
and structure of pharmaceutical advertising.
marketing materials, the primary constraint is word limit.
The assumption of good scientific knowledge allows text
to focus on concepts and details that may be particularly
relevant to a specialist field. Figures and tables are used
not only to summarise, but also to highlight key data.
Lay Audience
Given the condensed nature of direct marketing materials,
providing sufficient information for assessment of risk-benefit
as required by the PhRMA and ABPI codes of practice may
be daunting. However, the scientific knowledge inherent in
this audience may be exploited to minimise unnecessary
explanation. Lengthy paragraphs can be reduced to short
bullet points and ‘call out’ text can highlight key data.
The widespread use of electronic devices allows key data
to be supported by further detail that can be accessed
when required; however, high-level summaries must be
self-contained and remain accurate when more detailed
information is not displayed. Good design and layout are
critical, and close collaboration between experienced
writers and designers can ensure appropriate emphasis
is given to the information presented.
In contrast to direct marketing materials, articles in scientific
journals must provide detailed information that is sufficient for
replication of the reported work. Guidance to ensure legally
compliant, ethical and transparent publication of company
sponsored research is provided by the Good Publication
Practice (GPP) guidelines, developed by the International
Society of Medical Publication Professionals and first
published in 2003. The latest iteration (GPP3) was published
in 2015 and key principles include the reporting of clinical
trials in a “…complete, accurate, balanced, transparent, and
timely manner”, avoiding duplicate publication, appropriately
reflecting the collaborative nature of research, and defining
author and sponsor responsibilities (9). The GPP guidelines
have been widely adopted by medical journals, and updates
include changes to the criteria for authorship and clarification
of the role of professional medical writers.
Information for comprehensive reporting of randomised
clinical trials, as required by GPP3, is specified in the
Consolidated Standards of Reporting Trials (CONSORT)
Statement and checklist (10). Although adopted by many
medical journals, compliance with the CONSORT checklist
is frequently lacking in published articles (11). Increasingly,
supplementary information is made available online to
provide the required detail and transparency. Nevertheless,
inclusion of CONSORT-required information while adhering
to journal word counts and maintaining readability is often
challenging. It is perhaps unsurprising that the involvement of
professional medical writers may assist in achieving this (11).
Scientific posters and publications share common ground
with regulatory documents and direct marketing materials.
As for regulatory documents, comprehensive information
should be presented using a formal style. However, like direct
22
Historically, writing for the lay public has included patient
education materials, package leaflets, informed consent and
medical journalism. In all cases, text should be sensitive to the
needs of the reader while remaining engaging and interesting.
To account for variations in literacy levels and understanding,
simple language should be used and scientific terms,
acronyms and jargon avoided or explained.
Package leaflets and informed consent forms are documents
traditionally written for the layperson. However, there is
evidence that even these well-established documents may
be written at too high a reading level and may be improved
to increase patient understanding (12,13).
Alongside the more traditional writing for lay audiences,
the rapid development of web-based information
sources has resulted in greater patient demand for
healthcare information. In recent years, regulators and the
pharmaceutical industry have increasingly recognised the
importance of making information on healthcare products
accessible to the general public. Stakeholders and patient
organisations have indicated that although participants
are interested in the outcomes of the studies they entered,
they receive little if any subsequent information following
study completion. Notably, however, the most recent
iteration of the Declaration of Helsinki stipulates that “All
medical research subjects should be given the option of
being informed about the general outcome and results of
the study” (14).
Guidance
In the last decade, legislation in the US and EU has provided
for the dissemination of clinical trial summary data within
the ClinicalTrials.gov and EU Drug Regulating Authorities
Clinical Trials (EudraCT) databases, respectively, and has also
specified the production of clinical data lay summaries for
European RMPs and clinical trials.
Building on content outlined in European legislation for
clinical trials, a position document published by the European
Patient’s Forum proposed that the clinical trial lay summary
should also include (15,16):
• Details on study limitations, including steps to
address bias
•D
escription and rationale for study endpoints
•P
rotocol modifications
•D
etails of any patient engagement in the setting
of research priorities
Style, language and
literacy level to meet
the needs of the
general public
Follow health
literacy and
numeracy principles
Keep as short
as possible
Develop for a general
public audience
assuming no prior
knowledge of trial
General
Principles for
Writing Lay
Summaries
Focus on
unambiguous
factual information
Ensure no
promotional content
Involve patients
and their
representatives
in development
and review so the
summary meets
their needs
Source: Summary of clinical trial results for laypersons (17)
Figure 3: General principles for writing lay summaries recommended by the EU expert group on clinical trials
In 2016, the expert group on clinical trials provided a
consultation document outlining recommendations and
templates for those producing lay summaries for the EU
database (17). The general principles established in this
document are presented in Figure 3.
Healthcare literacy is possibly the biggest challenge in
presenting clinical data to the layperson. The expert group
recommendations indicate that text should be aimed at an
International Adult Literacy Survey proficiency level of 2-3
(ie low to average levels of literacy), corresponding to a Flesch
Reading Ease test score of 70 or higher, or a Flesch-Kincaid
Grade Level as close to 6th grade level as possible. Language
should be made accessible by avoiding complex sentences
and technical terms. Nevertheless, balancing accuracy
and understanding remains key in maintaining text that is
readable for the layperson. For example, when describing
neutropenia, an important safety concern for many drugs,
directly translating to ‘reduction in white blood cells’ may not
be sufficient. It may be necessary to explain that white blood
cells are responsible for fighting infection, and therefore a
reduction in these cells will make a patient more prone to
serious infection.
Of note, the recent EMA guidelines on the EU RMP (18),
anticipated to come into effect shortly, specifically indicate
that although the summary section “…should be written and
presented clearly, using a plain-language approach… this
Alongside the more traditional writing for lay audiences, the
rapid development of web-based information sources has resulted
in greater patient demand for healthcare information. In recent
years, regulators and the pharmaceutical industry have increasingly
recognised the importance of making information on healthcare
products accessible to the general public
23
does not mean that technical terms should be avoided”. This
guidance may seem contradictory to the perceived wisdom
that scientific terminology and jargon should not be used.
However, patients may benefit from understanding the medical
term that describes their condition and from awareness of
terms they may hear during medical consultations. In such
cases, a scientific term may be followed by a brief explanation.
Thus, writers should focus on avoiding excessive or unnecessary
use rather than eliminating all scientific terms.
10. Visit: www.consort-statement.org
11. Gattrell WT et al, Professional medical writing support and the quality of
randomised controlled trial reporting: A cross-sectional study, BMJ Open
6(2): e010329, 2016
12. Fage-Butler A, Package leaflets for medication in the EU: The possibility of
integrating patients’ perspectives in a regulated genre?, Medical Writing
24(4): pp210-214, 2015
13. Visit: www.ncbi.nlm.nih.gov/books/nbk133402
14. World Medical Association Declaration of Helsinki – Ethical principles
for medical research involving human subjects, JAMA 310(20):
Contrary to documents written for ‘expert’ audiences, use of
the active voice is appropriate in lay summaries (ie ‘doctors
treated patients’ rather than ‘patients were treated by doctors’).
Crucially, sentences must also maintain neutral, non-promotional
language. The European expert group recommendations on lay
summaries cite guidance from the Multi-Regional Clinical Trials
Center of Harvard and Brigham and Women’s Hospital Return of
Results Toolkit, produced to facilitate writing result summaries
in lay language (17,19). The Toolkit also contains a suggested
template, and clear guidance on neutral language, which is
reproduced in the recommendations.
pp2,191-2,194, 2013
15. Visit: www.ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/
reg_2014_536_en.pdf
16. Visit: www.eu-patient.eu/globalassets/policy/clinicaltrials/epf-laysummary-position-final_external.pdf
17. Visit: www.ec.europa.eu/health//sites/health/files/files/
clinicaltrials/2016_06_pc_guidelines/gl_3_consult.pdf
18. Visit: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_
and_procedural_guideline/2016/02/WC500202424.pdf
19. Visit: www.mrctcenter.org/wp-content/uploads/2015/11/2015-10-02MRCT-ROR-Toolkit-Version-2.0-2.pdf
Summary
The constant evolution in the requirements for healthcare
communication means that medical writers are continually
required to present vital information to an ever broader
range of readers. In targeting different audiences, a medical
writer must be able to adapt language, terminology and
presentation to communicate complex concepts and data
to the particular requirements of the reader. However, while
writers must be aware of the distinct differences in style
and content required, a commitment to clarity, accuracy
and quality is essential for effective and regulationcompliant medical writing, whatever the audience.
References
1. Visit: www.ema.europa.eu/docs/en_GB/document_library/Scientific_
guideline/2012/06/WC500129134.pdf
2. Visit: www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/
monograph/pmappe_mpanne-eng.php
About the authors
Kerry Walker is Director of Medical
Communications at Insight Medical
Writing. She obtained her PhD in Clinical
Endocrinology/Oncology from the
University of Wales College of Medicine.
Following a 12-year academic career
working closely with Astra Zeneca, Kerry joined the
pharmaceutical sector holding positions of increasing
responsibility within clinical departments at Amgen, Merck
and ConvaTec. She established Insight in 2002, having
identified a clear need for high-quality regulatory documents
within the industry. Kerry directs operations at Insight. She
has extensive experience of current regulatory, clinical
and marketing practices and has authored 45
medical publications.
3. Hamilton S et al, Developing the Clarity and Openness in Reporting: E3based (CORE) Reference user manual for creation of clinical study reports in
the era of clinical trial transparency, Res Integ Peer Rev 1(4), 2016
4. Visit: www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/
WC500174796.pdf
5. Kessel M, Restoring the pharmaceutical industry’s reputation, Nat
Biotechnol 32(10): pp983-990, 2014
6. Kesselheim AS et al, A randomized study of how physicians interpret
research funding disclosures, N Engl J Med 367(12): pp1,119-1,127, 2012
7. Visit: www.phrma.org/codes-and-guidelines/code-on-interactions-withhealth-care-professionals
8. Visit: www.pmcpa.org.uk/thecode/documents/code%20of%20practice%20
2016%20.pdf
Email: [email protected]
Nicola Evans is Senior Manager of Medical
Communications at Insight Medical
Writing. She holds a PhD in Molecular
Microbiology from the University of
Nottingham and a 1st Class BSc (Hons)
in Biochemistry from the University of
York. Following a period in academic
research, Nicola joined Insight as a Medical Writer. She has
over 15 years of diverse experience spanning EU and US
submissions, as well as a broad range of regulatory, clinical
and marketing documents across multiple therapeutic areas.
9. Battisti WP et al, Good publication practice for communicating companysponsored medical research: GPP3, Ann Intern Med 163(6):
pp461-464, 2015
24
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Clinical Study Protocols: How to
Write to Solve Problems Now and
Avoid Big Ones in the Future
Too many protocols are poorly written – wrought with inconsistencies in endpoint
descriptions, timing of assessments, approaches to gathering data – and lacking
consistency across the programme. The identification of different responsibilities,
under the clear leadership of the medical writer, is necessary to improve the quality of
clinical study protocols – to prevent problems and mistakes that can result later, during
conduct of the clinical trial, or afterwards, when reporting on trial results.
Historically, protocol generation has been the responsibility
of clinical and operations teams, who are understandably
focused on ensuring that the appropriate data are identified for
collection to support the study objectives and that the study is
initiated as quickly as possible, often with the mindset that any
inconsistencies will be corrected in future amendments. These
poorly written protocols present challenges both during the
study, when site personnel try to understand the requirements
of an inconsistent document, and after the study, when
clinical study report and submission document writers try to
understand, and are often forced to re-write inconsistent study
design and assessment descriptions.
By Kelley Kendle
at Synchrogenix
In addition to these existing challenges, the growing
requirements for disclosure and transparency are driving the
need for additional thought and care in protocol development
to ensure that the value of the information obtained in a study
is balanced with the patient experience. Protocols, historically
unlike any other regulatory document, have various audiences
such as the Private Investigator, study coordinator, regulator
and the patient at heart. Writing protocols consistently and
clearly, from the first version, requires ownership of the
process that understands the various goals of a protocol
document and can provide the consideration, quality, and
leadership that will ensure that these downstream challenges
Strategy and design
The protocol accurately reflects the objectives of the study. It is clear and consistent and has
the correct assessments to determine the success of the study
Ethics
The protocol has been drafted with ethical considerations in mind. The study takes into
consideration the patient experience and the concerns or reservations of individual patients
both for ethical reasons and to ensure feasibility of recruitment
Re-usability
The protocol is optimised for re-usability in downstream documentation. From registration
of the protocol to the extension of the protocol into the statistical analysis plan and clinical
study report, relevant considerations have been explored to address how the protocol is being
written for the ease of the next steps in documentation (eg description and selection
of endpoints) (see Figure 1)
Process/controls
Process and controls have been agreed upon and implemented. Decisions regarding
where the protocol will “live,” who owns the core protocol and amendment, strategies and
technology solutions for maintaining version control, and the process for obtaining approval
have been made and are being followed
Alignment
The protocol is aligned with all relevant company standards and associated documentation.
It is consistent with applicable style guidance, similar approaches and descriptions within the
same programme, the informed consent form (ICF), and the CRF. The protocol should be able
to function as the starting point for the lexicon for the entire programme, which should carry
all the way through to marketing application
Innovation
The protocol includes thoughtful input from multiple functions regarding both the design
and assessments as well as relevance of that design and those assessments across the
clinical programme (eg leveraging ideas across therapeutic areas and programmes, reducing
the tunnel vision of the clinical teams, exploring new tolerances by the regulatory health
authority (eg modelling and simulation to support some objective and end points), collecting
certain data that will be valuable to contribute to a future bridging analysis etc)
Time
Everyone on the protocol team has had the opportunity to spend the necessary time
and focus on performing the tasks that bring their highest value
Table 1: Fundamental goals of protocol writing
February 2017
l
25
Abstracts
Commercial Writing
Med
letters
Pubs
Posters
TLFs
Regulatory
Protocol
SAP
CSR
Submission
Life
Cycle
Narratives
Updates
Briefing Docs
Transparency & Disciosure
Lay Summary
Prospective Redaction and
Dataset De-identification
Registration
Source: Certara, 2015
Figure 1: Protocols are the foundation of the clinical programme
are minimal, re-usability of the content is high, and rework,
including additional clinical interpretation, is low.
“The first step in any clinical study is the protocol; if
that first step is organised, well-placed, and developed
with the downstream activities in mind, the rest of the
journey will go that much more smoothly”
Jen Moyers, Protocol Workstream Lead
Protocol creation, including document standards and
drafting processes, is part of an ongoing and lively debate
that generally exists between two camps: the clinical and
operations functions and centralised medical writing.
The clinical and operations functions own the content of
protocols and tend to prioritise study design elements and
consistency with other downstream documents (eg the case
report forms (CRFs) and risk monitoring plans), with a goal
of initiating the study as quickly as possible. In contrast, the
centralised medical writing functions tend to focus on internal
document consistency, clarity of thought, downstream
re-usability in other areas of the dossier, and adherence to
company standards. As always in these kinds of debates, the
two sides tend to focus on either/or solutions, where one
side is right and the other wrong, when a better solution
can usually be found somewhere in the middle. Ensuring
that the fundamental goals of the protocol remain the focus
throughout protocol development will help ensure
that a quality protocol is generated, from the first version.
These fundamental goals include those listed in Table 1.
26
With all of these fundamental goals to consider, it is clear
that there needs to be an understanding of the ownership
and value of each. The owners of process and content
knowledge are usually the medical writing or regulatory
functions. The clinical and operations functions are focused
on selecting the optimal design and getting the study
started, as they should be. However, the coordination of
efforts necessary for protocol creation, in addition to the
time commitment required, is often more than the clinical
and operations functions can handle in addition to their
existing priorities. Therefore, when these functions are
also the owners of a process, that process is frequently cut
short in an effort to progress the document, often leading
to unnecessary amendments and issues downstream in the
reporting phase. This can result in a study that generates
inconclusive data, extension of study timelines to collect
additional measurements, inconsistencies that require
explanation to health authorities, and more involved
quality assurance activities, all requiring additional costs
and potentially putting the programme at risk.
With the rise of patient centricity, there is also a need to
engage the patient community and advocates to enhance
feasibility and to get perspective on the key objectives and
the measures to which we are willing to go (or not to go)
to collect them. The role of clinical operations is critical to
drive this process, engaging with the patient community
and focusing on getting the clinical sites up and running.
Clinical trials are increasingly more complex, often weaving
collection of data for biomarkers, imaging biopsies,
Strategy and design
Ethical obligation and consideration
Coordination of the ICF and CRF
Alignment across programmes
Process and style
Lifecycle and communication of changes
Cross-functional review: transparency and disclosure
Table 2: Responsibilities to be assigned when preparing protocols
In the past few years,
we have seen an organisation
go from clinical and operations
protocol ownership and
resistance to medical writing
participation, to fully embracing
of the role of a medical writer in
the process, to finally creating
their own writing team focused
on protocol creation
and lifecycle
pharmacokinetics, etc into the classic objectives of a study.
For this reason, the clinical operations team needs to focus
on ensuring the planned activities of the study are feasible,
can be adhered to by study staff and participants, and align
with study goals. The medical writers will ensure these
activities are clearly and consistently communicated in
the protocol. It is imperative that both sides work together
as a cohesive team, trusting and relying on each other
to provide their respective inputs in the areas of their
particular expertise.
disclosure representative. This bridges the strength that a
medical writer can bring to the table (clarity, consistency,
adherence to process, coordination of reviews, balance
of objectives of speed and completeness, and creation of
the building blocks for downstream documentation) while
allowing the clinical and operations functions to be critical
reviewers, owning the design and feasibility, bringing in the
patient perspective and understanding of the disease, and
focusing on the training and set up of sites. This also allows
for coordination across studies if amendments are needed
once a study has been started.
Regardless of your organisation’s size, it is critical that you
clearly define the necessary responsibilities and owners.
Consider who in your organisation would be considered
the owner of the responsibilities listed in Table 2.
For most protocols, a combination of functions/
roles is responsible and accountable for each of these
responsibilities. Determining the owners of each and
realising that these fundamental elements will carry
through the programme for the length of its existence
is critical. Focusing on the fundamental goals for your
protocol, defining responsibilities, and identifying owners
will ensure that quality protocols are generated, without
the need for amendments… solving problems now and
avoiding them in the future.
About the author
In the past few years, we have seen an organisation go from
clinical and operations protocol ownership and resistance
to medical writing participation, to fully embracing of the
role of a medical writer in the process, to finally creating
their own writing team focused on protocol creation and
lifecycle. This not only shows the value of the medical
writer contribution to improving clarity and the ability to
meet timelines, it also shows that including perspective
outside of the study team can bring valuable insights and
innovation to the study design and conduct.
A long-tenured executive with
Synchrogenix and a strategic regulatory
solutions provider, Kelley Kendle
possesses a keen understanding of the
regulatory landscape, coupled with a
strong focus on client relationships. She
has been instrumental in developing
solutions to address the industry's needs. With over
15 years of experience in drug development, Kelley is
both an internal and external subject matter expert. As
President, she is responsible for driving Synchrogenix's
strategic growth, including mergers and acquisitions,
business process, and organisational dynamics.
In addition, the integration of a medical writer into protocol
writing often includes the review of the ICF and CRF,
and cross-functional reviews including a transparency/
Email: [email protected]
27
Medical Writing: The Backbone of Clinical Development
Streamlining Clinical Study
Protocols and Reports
Recent pharma initiatives have been established to help ensure that clinical
study protocols and reports are always presented in a similar way, making for
easier assimilation and assessment. This article discusses these initiatives,
and outlines their key recommendations.
As we have seen in earlier articles in this magazine, ICH guidelines
help ensure that the same critical types of information are included
in appropriate clinical documentation (including clinical study
protocols [CSPs] and clinical study reports [CSRs]), but they do not
guarantee that this information is always presented in a similar way.
This means that regulatory reviewers have to interpret numerous
documents about all kinds of medicines, which may differ not only
because of their specific therapeutic area content requirements,
but also because information requirements that are common
across programmes are presented in different ways. It is therefore
difficult to gain a clear understanding of the data generated across
an industry. The effort needed to extract and compare data from
one programme to the next – even within a single therapeutic
area – can be enormous. Despite this, the reviewer must assess
if each new drug would be a valuable addition to the existing
armamentarium of medicines.
In the past 12 months, two initiatives have come to fruition that
will help streamline the writing of CSPs and CSRs. These are
the TransCelerate Common Protocol Template (CPT) and the
By Sam Hamilton at
Sam Hamilton Medical
Writing Services and Julia
Forjanic Klapproth at Trilogy
Writing & Consulting
CORE (Clarity and Openness in Reporting: E3-based) Reference.
Both aim to produce CSPs and CSRs of common structure and
layout, with standard information in just one, consistent place.
They aim to simplify the review task enormously and improve
transparency, making it immediately apparent if information is
missing or incomplete. The goal is to save time in developing
documents and in drug development generally, as writing
teams dispense with discussing options for the structure of
the standard elements of a particular document, and focus on
content. So is this a pipe dream?
TransCelerate Common Protocol Template
The new CPT was issued by TransCelerate in December 2015
(1). The TransCelerate group is a collaboration between
industry stakeholders and regulators who had the idea of
producing a definitive template for the CSP, regardless of the
type of treatment or therapeutic area being studied. Each
company approaches CSP writing slightly differently: should
the description of all the variables be in the statistics section
What is the TransCelerate CPT?
The CPT is a detailed protocol template, including pre-prepared headings and draft text, in Microsoft Word format. It is intended to
be used directly by authors of CSPs for any kind of clinical study, involving any kind of medical condition or therapy. The goal is that all
protocols present equivalent information in a similar manner. The Word template contains sections marked as common text or text
that may be employed across CSPs with little to no editing if the author so chooses. Clearly, the use of the template is at the discretion
of the author.
For the preparation of a CSP, the CPT implementation toolkit includes the resources listed in the table below (2):
Resource
Description
Comments/value of using
Word CPT
Guidance for use
A detailed Word document that contains instructions
and brief videos demonstrating selected steps in the
use of the technology-enabled edition of the CPT
Provides understanding of the functionality found in the
technology-enabled edition of the CPT
Frequently asked questions
Frequently asked questions and responses about
the CPT, how it was developed and how it will be
maintained
Access to responses on common questions
Mapping exercise – instructions
and worksheet
A tool to facilitate comparison of an existing protocol
template to the CPT
Allows for section-by-section identification of differences
in headings and content to aid in assessing impact of
implementation and possible mitigations needed
Stakeholder map
A customisable tool to assess the impact that
implementation of the CPT may have on each
stakeholder group
Allows those implementing to plan for appropriate training and
communication needs
Text colour guide
Colour coding used within the CPT to distinguish
common, suggested example and instructional text
Provides understanding of the meaning of colour coding used
28
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February 2017
or in the investigational plan section? Where should details
of the various parties involved in performing the clinical
study appear – in an appendix, at the front or somewhere in
the middle? As long as the information is there, its location is
immaterial – as evidenced by the fact that CSPs are approved
and the studies run, despite all this variation. So why not
agree on one approach, and use the time saved to focus
on other, more important things? Training medical writers
would be less time-consuming; writing and review time
would also be shortened.
So what does the TransCelerate CSP template give us? At a
minimum, it offers a model CSP template defining a common
structure and standardised language. Its intended use with
libraries of common language in areas specific to patient
populations and therapeutic areas means that the pre-crafted
text proposals for many sections will be the same across CSPs.
Ultimately, the industry can save the time spent pondering
redundancies and instead focus on study-specific content. Coauthor and end user review will be streamlined as familiarity
with these standardised texts grows. Regulatory reviewers
will more rapidly navigate to the meaningful, study-specific
content and comparison of CSPs across programmes will
be enhanced, such that the input from ethics committees/
institutional review boards and regulators will be more
focused. Investigators and study staff will more readily find the
information they need, which may translate to efficiencies in
terms of study performance.
CORE Reference
Another new tool – released in May 2016 for CSRs – is CORE
Reference, designed to streamline the way the industry
structures and populates a CSR. The international basis
for CSR content is laid out in the 1995 ICH regulatory
guidance document ICH E3 on the structure and content
of CSRs (3), and the 2012 ICH E3 supplementary Q&As (4).
However, any guidance or reference material is reflective of
a static time point and, back in 1995, clinical studies were
simpler than they are today. Modern clinical study designs
often integrate pharmacokinetic, pharmacodynamic,
pharmacoeconomic and pharmacogenomic elements with
a safety and efficacy backbone. Today’s clinical studies
need a fit-for-purpose reporting framework that may differ
What is CORE Reference?
CORE Reference is a user manual to help medical writers navigate guidelines
as they create CSR content relevant for today’s studies. It comprises a preface
followed by the actual resource, which includes the following:
• Text from the original ICH E3 guidance document is shown in unboxed
grey shading
• Text from the ICH E3 Q&A 2012 guidance document is shown italicised,
grey shaded and boxed
• CORE Reference text is not shaded and not boxed
A separate mapping tool compares ICH E3 sectional structure and
CORE Reference sectional structure. Together, CORE Reference and the
mapping tool constitute the user manual (5).
So what does the
TransCelerate CSP template
give us? At a minimum, it
offers a model CSP template
defining a common structure
and standardised language.
Its intended use with libraries
of common language in
areas specific to patient
populations and therapeutic
areas means that the
pre-crafted text proposals
for many sections will be
the same across CSPs
substantially from the more straightforward efficacy and
safety studies of 20 years ago, which ICH E3 set
out to support.
The ever-growing regulatory guidances dictate additional
content requirements that must be worked into CSRs. The
medical writer must be extraordinarily diligent and well
informed to keep pace. Specifically, public disclosure of CSRs
– now mandated in the EU – has profound effects on the
way that we must write CSRs. EMA guidance on preparing
clinical data for disclosure explains that because redaction
alone will “decrease clinical utility of the data compared to
other techniques”, it strongly encourages the move towards
proactive anonymisation techniques (6). The impacts on the
CSR are multiple and complex, and lessons will be learnt as
CSRs are disclosed.
Key Areas in which CORE
Reference adds to ICH Guidelines
CORE Reference makes content suggestions for the primary use CSR
(the EMA term is ‘scientific review version’). Comments are used to
indicate individual report text portions that may potentially impact
the secondary use CSR (the EMA term is ‘redacted clinical report’) and
should, therefore, be considered for redaction in the secondary use CSR
– for public disclosure.
CORE Reference mapping tool provides the sectional structure of CORE
Reference, but the important areas where CORE Reference advises
restructuring and greater granularity of CSRs are as shown in the table
which follows:
29
ICH E3 section
Key CORE Reference section differences
8 – Study Objectives
New granularity:
8.1 – Objectives
8.2 – Endpoints
9.4.1 – Treatments Administered
New granularity:
9.4.1.1 – Investigational Products
9.4.1.2 – Non-Investigational Products
9.5.1 – Efficacy and Safety Measurements Assessed and Flow Chart
New granularity:
9.5.1 – Efficacy and Safety Measurements Assessed and Schedule of
Assessments
9.5.1.4 – Safety – Adverse Events
9.5.1.5 – Safety – Clinical Laboratory Evaluation
9.5.1.6 – Safety – Vital Sign Measurements
9.5.1.7 – Safety – Physical Examination
9.5.3 – Pharmacokinetic and Pharmacodynamic Measurements
9.5.3.2 – Pharmacokinetic Parameters
9.5.3.3 – Pharmacodynamic Measurements
9.5.3.4 – Pharmacodynamic Parameters
9.5.4 – Other Measurements
9.7.1 – Statistical and Analytical Plans
New granularity:
9.7.1 – Statistical Plans
9.7.1.1 – General Approaches
9.7.1.2 – Primary Efficacy Endpoint Methodology
9.7.1.3 – Secondary Efficacy Endpoint Methodology
9.7.1.4 – Other Efficacy Endpoint Methodology
9.7.1.5 – Safety Endpoint Methodology
9.7.1.6 – Pharmacokinetic and Pharmacodynamic Endpoints Methodology
9.7.1.7 – Other Endpoint Methodology
9.8 – Changes in the Conduct of the Study or Planned Analyses
New granularity:
9.8.1 – Changes in the Conduct of the Study
9.8.2 – Changes in the Planned Analyses
9.8.3 – Changes Following Study Unblinding and Post-hoc Analyses
11.1 – Data Sets Analysed (Efficacy Section)
Moved to 10.3 – Data Sets Analysed – new Study Subjects, Section 10
11.2 – Demographic and Other Baseline Characteristics (Efficacy Section)
Moved to 10.4 – Demographic and Other Baseline Characteristics – new
Study Subjects, Section 10. New granularity added:
10.4.1 – Demography
10.4.2 – Baseline Disease Characteristics
10.4.3 – Medical History and Concurrent Illnesses
10.4.4 – Prior and Concomitant Treatments
11.3 – Measurements of Treatment Compliance (Efficacy)
Moved to 10.5 – Measurements of Treatment Compliance in Study Subjects –
new Study Subjects, Section 10
11.4 – Efficacy Results and Tabulations of Individual Patient Data
Becomes Section 11.1 – Efficacy Results
11.4.1 – Analysis of Efficacy
Becomes Section 11.1 with new granularity:
11.1.1 – Primary Efficacy Endpoint
11.1.2 – Secondary Efficacy Endpoints
11.1.3 – Other Efficacy Endpoints
11.1.4 – Post-hoc Analyses
11.4.6 – By-Patient Displays
Not included
12 – Safety Evaluation
ICH E3 Section 12.1 – Extent of Exposure – becomes CORE Reference Section
10.6 – Extent of Exposure – new Study Subjects, Section 10
(Remainder of Section 12 renumbered accordingly; some
additional granularity)
12.2.4 – Listing of Adverse Events by Patient
Not included
12.5 – Vital Signs, Physical Findings, and Other Observations Related to Safety
Becomes Section 12.4 due to renumbering (see above), with new granularity:
12.4.1 – Vital Signs
12.4.2 – Physical Examination Findings
12.4.3 – Other Observations Related to Safety
13 – Discussion and Overall Conclusions
New granularity:
13.1 – Discussion
13.2 – Conclusions
Annexes
Annexes I, IIIa, IIIb, IVa, IVb, and VII adapted and moved into the
document body
30
In short, writers must create CSRs that support
heterogeneous study design and cover all emergent
content requirements, including public disclosure
requirements. ICH E3 and the 2012 Q&A allow flexibility in
CSR structuring to suit individual study design. Without a
common approach, designing a logical CSR framework for
individual studies inevitably results in variable
report structures.
and culture – if we can overcome personal preferences
and aspire to a higher goal of true standardisation, it could
simplify processes, reduce the cost of developing drugs
and accelerate getting them to market. This would be real
progress that benefits patients.
CORE Reference is an open-access “user manual to help
medical writers navigate relevant guidelines as they create
CSR content relevant for today’s studies” (5). It is not a
template; rather, it presents the focused guidance-required
content with other value-added insights, and organises it
all into a logical presentational sequence. CORE Reference
additionally suggests intelligent anonymisation approaches
that will minimise redaction requirement in the publicly
disclosed CSR, and pinpoints these within individual CSR
suggested sections. In focusing on content and providing
suggested common structure, CORE Reference facilitates
a content-driven document that is as disclosure-ready as
possible. With sufficient uptake, it has the potential to drive
standardisation of CSR writing across the industry.
References
This article has first been published in WorldPharma, Clinical Trials
Insight (2), 2016 and has been amended for this supplement.
1. Visit: www.transceleratebiopharmainc.com/initiatives/
common-protocol-template
2. Visit: www.transceleratebiopharmainc.com/assets/
common-protocol-template
3. Visit: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Guidelines/Efficacy/E3/E3_Guideline.pdf
4. Visit: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Guidelines/Efficacy/E3/E3_QAs_R1_Step4.pdf
5. Visit: www.core-reference.org/core-reference
6. Visit: www.ema.europa.eu/docs/en_GB/document_library/
Regulatory_and_procedural_guideline/2016/03/WC500202621.pdf
7. Visit: www.researchintegrityjournal.biomedcentral.com/articles/
10.1186/s41073-016-0009-4
8. Visit: https://s3.amazonaws.com/public-inspection.federalregister.
Collateral impacts on the overall drug licensure process from
efficiencies gained on individual CSR structural planning
and content considerations should positively impact time
to market and development costs. Of course, any resource
can only remain relevant if it is updated on an as needed
basis. This is a stated aim for CORE Reference (7). Indeed,
CORE Reference end users (including CROs and pharma)
are beginning to report on the utility of CORE Reference to
develop their existing CSR templates. The website supports
sharing of disclosure feedback received from the EMA, and
this will be fed back into the project to provide industry-wide
insight on how best to make each CSR meet the
EMA’s expectations.
Some four months after CORE Reference was launched, the
US Department of Health and Human Services published
the Final Rule on clinical trials registration and results
information sharing – effective from 18 January 2017 –
which mandates posting of clinical trial results information
on CT.gov (8). Although the detailed requirements will
not impact results reporting in CSRs per se, signposting to
these requirements (as already done for similar EudraCT
results posting requirements) in a future version of CORE
Reference will add tangible value in managing registry
postings alongside the writing of CSR results content.
Conclusion
In an industry crying out for standardisation of its
documents, these two valuable tools will help streamline
the production of two essential documents, the CSP and
the CSR. Although in some quarters they may not be seen
as perfect – because they break with long held convention
gov/2016-22129.pdf
About the authors
Sam Hamilton is a postdoctoral virologist
and director of her UK-based consultancy,
Sam Hamilton Medical Writing Services.
With 22 years of experience in clinical
and medical writing roles in the pharma
industry, she has written numerous
clinical-regulatory document types for
all phases of studies and all genres of client. Sam was
European Medical Writers Association (EMWA) president,
serving two years (2014-2016) on the Executive Committee
and is Chair of the CORE Reference project.
Email: [email protected]
After receiving her PhD in Developmental
Neurobiology, Julia Forjanic Klapproth
started her career as a medical writer in
the regulatory group at Hoechst Marion
Roussel (later Sanofi) in 1997. Since
then, she has been president of the
European Medical Writers Association
twice. In 2002, Julia co-founded Trilogy Writing &
Consulting Ltd, a company that specialises in providing
regulatory medical writing. In addition to managing the
company as Senior Partner, she writes a wide array of
clinical documents including study protocols, study
reports, and the clinical parts of CTD submission dossiers.
Email: [email protected]
31
Medical Writing: The Backbone of Clinical Development
The Challenge of CTD Submissions
and Responding to Questions from
the Authorities
The Common Technical Document is an international standard for the summary
documents needed to obtain regulatory approval of medicinal products.
These summary documents involve presenting key information drawn from a
large body of data, with input from a range of stakeholders within a project
team. The challenges involved in preparing a CTD submission are numerous,
and for medical writers will vary according to dossier size, team experience,
data complexity and time available. By having insights on all these aspects
and proactively seeking pragmatic solutions to issues as they arise, medical
writers can guide the project team towards the goal of delivering the final set
of summary documents within the agreed timelines.
The Common Technical Document (CTD) is not a single
document as the name implies, but an international standard
published by the ICH that specifies the structure, content and
format of summary documents used for obtaining regulatory
approval of medicinal products.
The standard covers the entire spectrum of documentation to
be included in a regulatory submission dossier, and provides
guidance on how formulation and manufacturing information
(‘quality’) as well as the results of non-clinical and clinical
research should be organised and presented. The submission
dossier is divided into five modules. Conceptually, the overall
structure can be regarded as a pyramid, with study reports
providing the most detail at the base and an increasing level
of summarisation towards the apex (see Figure 1).
The highest level of summarisation is the region-specific
prescribing information, the ‘label’, included in Module 1.
The components included in Modules 1-5 vary according to
the type of approval being sought, eg from a large, complex
dossier for a new chemical entity to a small, straightforward
dossier for a label change. From a medical writing perspective,
the authoring involved in preparing a CTD submission is
typically for the summary documents included in Module 2.
The electronic CTD (eCTD), which is based on the CTD, is the
electronic standard published by the ICH for organising and
submitting CTD documentation to regulatory authorities.
From the medical writing perspective of the summary
documents in Module 2, there is no difference between
a CTD submission and an eCTD submission.
Preparation of a CTD is often regarded as the epitome of
regulatory medical writing due to its complexity and the
experience needed. The challenges involved are numerous,
32
l
February 2017
By Douglas Fiebig at Trilogy
Writing & Consulting
and for medical writers vary according to dossier size, team
experience, data complexity and available time. Typically,
the challenges confronting medical writers preparing a CTD
are similar irrespective of whether they are summarising
manufacturing information (based on Module 3), non-clinical
information (based on Module 4) or clinical information
(based on Module 5). In all but the smallest dossiers, these
areas will likely be covered by separate medical writers or
separate teams of medical writers. The focus of this article is
on medical writing needed for preparing and summarising
clinical documentation, which typically constitutes the
largest part of a submission dossier.
The Team Approach
Substantial hands-on experience of writing regulatory
documents through to completion is an essential prerequisite
for medical writers working on a CTD. To lead the medical
writing effort, the writer must have substantial experience of
writing CTDs (not just reviewing them), because this is the only
way to gain the experience needed to visualise the finalised
dossier and manage the multiple work streams required to
achieve it. Support writers should, at least, ideally have had the
hands-on experience of writing other regulatory documents,
such as clinical study reports and investigator brochures.
For a larger dossier, the lead writer will typically need to
assemble a team of writers with responsibility for writing
various components of the clinical documentation. In
this constellation, the clinical summaries (Module 2.7),
encompassing the four key topics of biopharmaceutics, clinical
pharmacology, efficacy and safety, may each require a separate
writer. Each of these writers may also contribute to the clinical
overview (Module 2.5), or the clinical overview may need a
dedicated writer.
Not part
of the CTD
Regional
administrative
information
Module 1
Non-clinical
overview
Module 2
Clinical
overview
The CTD
Quality overall
summary
Quality
Module 3
Non-clinical
summary
Clinical
summary
Non-clinical study
reports
Module 4
Clinical study
reports
Module 5
Source: www.ich.org/products/ctd.html
Figure 1: The CTD pyramid describing the organisation of a regulatory submission dossier
At this stage, it already becomes clear that the lead writer plays
a key role in project logistics. The individuals on the writing
team may each be interacting with different members of the
project team as a whole (eg representing the clinical, clinical
pharmacology, statistics, regulatory and non-clinical functions),
and close coordination of the writing team is required from
the outset to ensure scientific and technical consistency across
the dossier. An example of the potential complexity of a CTD
– including interconnectivity between documents and the
overview that the lead writer needs to maintain throughout the
process – is provided in Figure 2.
writers, whether leading or supporting, must understand
the aims of the clinical programme in the context of the data
available or expected, and must be in a position to advise the
project team on interpretation of the regulatory guidance
for writing CTD summaries. When the project team has little
or no experience of submission dossiers, the medical writer’s
experience can be crucial for advising on how to apply the
guidance to achieve not only effective document structure
and data presentation, but also an effective process for
preparing the documentation.
Key Messages
A first step in this coordination is a series of kick-off meetings,
which aim to clarify details of the dossier and drive the design
of the shells for individual summary documents. Medical
As early as possible in the project, medical writers must ensure
that the project team agrees on key messages and how these
Preparation of a CTD is often regarded as the epitome of
regulatory medical writing due to its complexity and the experience
needed. The challenges involved are numerous, and for medical
writers vary according to dossier size, team experience, data
complexity and available time
33
Project team
CP
C
R MW
NC
S
CMC
C
S
R MW
CP
NC
C
S
R MW
CP
NC
CMC
2.7.1
BIOPHARMACEUTICS
Shell
D1
D2
Final
2.7.2
CLINICAL
PHARMACOLOGY
Shell
D1
D2
Final
2.7.3
EFFICACY
Shell
D1
D2
Final
2.7.4
SAFETY
Shell
D1
D2
Final
2.5
CLINICAL OVERVIEW
Shell
D1
D2
Final
C = clinical; CMC = chemistry, manufacturing, and controls (“Quality”); CP = clinical pharmacology;
D = draft; MW = medical writer; NC = non-clinical; R = regulatory; S = statistics.
Vertical lines indicate time points when consistency between documents is checked, depending on the status of their preparation. The figure provides only
an example of interconnectivity between documents and is not definitive; the actual degree of interconnectivity between documents and the timing of
ensuring consistency between documents is project-specific and will vary between submissions
Figure 2: Conceptual illustration of multiple work streams when preparing clinical summary documents for a
CTD submission, including interconnectivity
can be effectively communicated. The correct time point for
this will vary according to availability of data and between
summary documents. Even when pivotal data have yet to
be provided, key message scenarios can be developed in
alignment with the envisaged prescribing information.
Key messages are akin to defining the destination of a journey.
The challenge for medical writers is often to focus the project
team on defining these sufficiently early so that the best
route for reaching the destination can be mapped. While this
sounds obvious, project teams are often surprisingly hesitant
to commit to key messages early in a project, and often prefer
to leave their options open for as long possible even when,
with hindsight, this is rarely necessary. For medical writers,
this form of procrastination can result in multiple changes
in direction, with all the ensuing inefficiencies in document
preparation – including a substantial drain on the team’s
ability to reflect on data and provide effective input.
Having aligned the project team on the issues above, the
next challenge for medical writers is the practical task of
crystallising out essential facts and interpretations from the
mass of data included in the dossier. Starting at the base of
the CTD pyramid, if the study reports are well written then
they should include key messages regarding interpretation
of the individual studies concerned. However, it is common
for medical writers to have to revisit a poorly written report
to establish exactly what the key message of the study is.
34
The clinical summaries (one level up from the study reports)
are intended to summarise information from individual studies,
as well as provide a perspective across studies. The approach
needed varies across the four key topics in Module 2.7.
Take, for example, safety information: adverse events
from the clinical studies may need to be summarised
individually by study, together with an integrated analysis
of the adverse events across these studies. The challenge
for medical writers is to ensure that at the clinical summary
level, only key facts relevant to supporting the prescribing
information are included and that essential messages are
not muddied by inclusion of unnecessary information.
This can be a substantial challenge, because some teams
are reluctant to prioritise facts, instead preferring to include
as many facts as possible in a clinical summary to ‘be on
the safe side’.
The clinical overview (Module 2.5) – yet another level
removed from the study reports that is intended to discuss
strengths and weaknesses across the clinical programme
to justify the prescribing information within a space of
approximately 30 pages – should provide an even higher
level of summarisation than the clinical summaries.
Medical writers often need to remind the project team that
their audience for the clinical summaries and the clinical
overview is primarily made up of regulatory reviewers
Medical writers often need to remind the project team that
their audience for the clinical summaries and the clinical overview is
primarily made up of regulatory reviewers charged with assessing
suitability of the medicinal product for approval
charged with assessing suitability of the medicinal product
for approval. In this context, every piece of information that
is proposed to be included in these documents must be
examined for its relevance in supporting the prescribing
information. Not including a fact in a clinical summary is not
synonymous with hiding that fact, because the study reports
in Module 5 provide complete disclosure of all the
data accrued in the clinical programme.
Planning and Review Workflows
The assembly of a writing team, coordination of writing
activities and maintenance of writing standards provide the
lead writer with a substantial logistical challenge. There is also
a further challenge involved in planning and maintaining the
timelines for reviewing CTD component documents, which
must also take account of the interdependencies between these
documents shown in Figure 2. The worst scenario is a timeline
designed without the input of medical writers, especially the
lead medical writer. Unless someone has actually written a CTD,
they are ill placed to design the timelines for preparing a CTD,
because they may not understand the critical nodes and knockon effects of changes in the timing of individual components.
The most effective approach is for the project planner to consult
all document stakeholders in the project team – particularly
the medical writers – while drawing up the timelines, and these
should be regularly revisited and fine-tuned, with buy-in by all
stakeholders as needed as the CTD progresses.
or eliminate the need to revisit such issues at a later stage. An
essential element is effective planning of the reviewing time
slots for all reviewers – including reserving time in calendars
– so that a realistic amount of time is available for reviewing
with a minimum of conflicts with other activities. If a member
of the project team needs to review multiple documents
within an unrealistic timeframe, the reviews will not receive
the attention they deserve; issues will not be addressed
appropriately; and unaddressed issues will stack up later in the
document preparation process when the least amount of time
is available.
A further challenge for medical writers is document
review by senior management. In part, this is influenced
by company culture, which can range between senior
management having full faith in the project team and feeling
the need to provide only minimal input to preparation
of the CTD, to senior management providing extensive
input. The quality and relevance of this input can vary
considerably, and may or may not be helpful. For medical
writers, the situation can become a substantial challenge
when senior management input is added at the later stages
of document review, especially when earlier decision-making
is overturned. Medical writers with a wealth of experience
can often sense when such a situation may arise, and will
urge the project team to include senior management in early
review rounds in an attempt to mitigate the situation.
Completing the Submission Package
Even with the best planning, somewhere among all the
moving parts there will almost certainly be delay beyond
the writer’s control, eg due to delays in planned analyses
or the need for additional analyses. Time is always at a
premium, and timelines are more likely to be truncated than
extended. It is, therefore, crucial to ensure that the original
plan is realistic, and buffers and mitigations for rate-limiting
steps should be identified that can be used if and when the
timelines need to be adjusted.
Having a project plan is one thing, but enforcing it can be
quite another. For medical writers, the critical logistical aspects
that are almost universally challenging while preparing CTDs
are the timely provision of source information; an effective
process to conduct the review within a single file; buy-in by
all stakeholders that the reviews can and will be conducted
within the agreed time slots; and a commitment to decide on
the resolution of critical review issues as they arise to minimise
Depending on the complexity of the submission, preparation
of the CTD and the ensuing review cycles can be a lengthy
process, but at some stage the summary documents must be
finalised. In the later stages of preparation, medical writers
play a key role in ensuring that all stakeholders are satisfied
with the documents, and that these are factually correct and
technically coherent. For the lead writer on the submission,
the challenge is maintaining contact with project subteams across the four key topics of biopharmaceutics,
clinical pharmacology, efficacy and safety, reviewing their
documents through all stages of preparation. This ensures
consistency of message and presentation across documents.
In the final review round, the lead writer must ensure that all
the CTD summaries are consistent between the individual
clinical summaries (Module 2.7), and between these and
the clinical overview (Module 2.5) as well as the proposed
prescribing information.
35
The questions posed by regulatory reviewers vary from
straightforward technical queries to requests for new analyses or
further interpretation of existing analyses. Questions regarding
interpretation of data will usually require medical writers in the
project’s rapid response team, with a central role in crafting responses
and in coordinating input from the various stakeholders involved
Irrespective of whether medical writers are responsible for the
entire dossier or one or more component summaries, they are
most effective when they operate in a role best summarised
as ‘the glue that holds it all together’, ensuring that the various
interests of all stakeholders are taken into account in the
documents being prepared. Medical writers must ensure
that all content issues have been resolved, and that the final
document is delivered in a timely fashion.
Medical Writing after Dossier Submission
A common challenge for many project teams is their
tendency to disband after the CTD dossier has been
submitted. This is unfortunate, because often there is
a substantial requirement for document authoring and
preparation before a regulatory decision is received.
Almost all development programmes contain certain
weaknesses or other issues of concern for regulators,
generating questions during review of the dossier. In
Europe, these questions come at predefined time points
– 80 days after dossier acceptance for draft questions
and after 120 days for final questions – while in the US,
questions may come at any time after dossier acceptance.
The questions posed by regulatory reviewers vary from
straightforward technical queries to requests for new
analyses or further interpretation of existing analyses.
Questions regarding interpretation of data will usually
require medical writers in the project’s rapid response
team, with a central role in crafting responses and
in coordinating input from the various stakeholders
involved. Ideally, the same medical writers and other
stakeholders who prepared the CTD should also be
available in the post-submission period, so that their
legacy knowledge is available when a rapid turnaround is
needed for responding to questions.
Thought should also be given soon after the dossier has
been submitted to proactively assessing weaknesses in
the clinical programme, and any potential questions that
may arise even before they are raised. Time invested at this
juncture can pay dividends when questions are received
and responses are required in a short timeframe.
36
The challenge for medical writers is to focus the project
team on providing input for addressing questions that
have yet to be officially posed. Here, medical writers can
facilitate the process by proposing pragmatic means of
capturing thoughts on topics, eg via text or bullet points in a
spreadsheet, together with other practical information such
as the status or location of any additional analyses needed.
Medical writers can also be effective in supporting the team
in preparing materials (briefing documents and presentation
slides) for an oral explanation meeting in Europe or an FDA
Advisory Committee meeting in the US – events that can be
instrumental for the decision on regulatory approval.
Conclusions
Medical writers, with their central role in preparing the
summary documents needed for a CTD submission, face
numerous challenges depending on dossier size, team
experience, data complexity and available time. By having
insights on all these aspects and proactively seeking pragmatic
solutions to issues as they arise, medical writers can guide the
project team towards their goal of delivering the final summary
documents within agreed timelines. An overall challenge for
medical writers is to remain focused and diplomatic at all times,
understanding that they are likely not the only members of the
team under intense pressure to complete the CTD on time.
About the author
With a PhD in Environmental Microbiology,
Douglas Fiebig joined Hoechst (later
Aventis) as a Medical Writer in 1996 and
has since been involved in preparing
the entire spectrum of clinical regulatory
documentation. He co-founded Trilogy
Writing & Consulting in 2002 and has
prepared regulatory documents for many large and small
pharmaceutical companies. Douglas’ main focus has been
on organising and writing CTD submission summaries, often
also providing the medical writing support needed after the
dossier has been submitted.
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Getting Clinical Research
Results Published
The goal of clinical research is to provide doctors with a better understanding
of treatment options and, ultimately, to improve medical practice. Achieving
this depends on research results reaching policy makers, doctors, and other
researchers via peer-reviewed journals. For many researchers, however, the path
to successful publication is not clear, and the process can be time-consuming
and stressful. In this article, we outline key concepts and steps in organising,
preparing, and successfully publishing clinical research articles.
To make good treatment decisions, doctors require a sound
evidence base and therefore the complete, accurate, and
timely reporting of medical research. Conversely, incomplete,
inaccurate, misleading, or delayed reporting can damage
the quality of healthcare.
Good Publication Practice (GPP), created in 2003 by the
International Society for Medical Publication Professionals
(ISMPP), is the main ethical standard “for individuals and
organizations that contribute to the publication of research
results sponsored or supported by pharmaceutical, medical
device, diagnostics, and biotechnology companies” (1,2). GPP3,
the most recent version, recommends that the results of all
clinical studies, even non-interventional studies, should be
published in a peer-reviewed journal (2). This includes not only
positive but also negative or inconclusive results, as well as all
research on interventions that are investigational, licensed, or
even have been discontinued or withdrawn from the market.
GPP3 also insists that in cases where a study does not produce
publishable data, the results should still be posted on a public
website, such as ClinicalTrials.gov.
Start the Article off on the Right Foot with a
Kick-off Meeting and an Organised Writing Process
Writing a publishable article is a challenge even for the
most experienced writers, but just as challenging is keeping
the entire process on track, on time, and on budget.
Usually, publications are collaborative, multidisciplinary,
multinational projects. In such a complex environment, a
variety of communication problems can cause the project
to go off track. Avoiding these problems requires an
organised plan, not just for the writer but also for the
whole team.
Start with a Kick-off Meeting
Kick-off meetings are time well spent. This is where the
direction is set for the entire project. The kick-off meeting
should include discussions and decisions about the key
messages and data to include, how the writing process will
proceed, who will participate and at which points in the
By Phillip S Leventhal
at 4Clinics and Stephen
Gilliver at TFS
• Agree on messages/focus
• Discuss ideas for target journal
• Define roles
• Decide on timelines
• Organise review process
Figure 1: Agenda for a kick-off meeting
process, what journals might be targeted, and when different
steps in the process should be completed (see Figure 1).
The Participants and the Venue
The kick-off meeting does not need to include everyone
involved in the project, just the major players, typically the
writer, the project manager, and the lead investigator or another
knowledgeable investigator. More people can be added, but
increasing the number of participants generally complicates
decision-making and unnecessarily prolongs the meeting. Kickoff meetings can be via teleconference or web interfaces like
WebEx and Skype for Business, although a face-to-face meeting
can improve interpersonal relations and thereby help avoid
miscommunication and conflicts between team members.
Present the Study Design and Results
In many cases, the lead investigator and main writer are
not the same person. Frequently, a professional writer is
involved. The kick-off meeting should therefore include a
presentation by the lead investigator to help familiarise
the writer with the study design and findings. Such a
presentation also serves as the basis for a discussion
of key messages and key data to be presented.
Discuss Ideas for the Target Journal
The kick-off meeting is an opportunity for the writer to ask
whether the investigator and project manager have ideas for
the target journal. As part of this, the writer should ask about
the motivation for choosing a particular journal. An experienced
writer can help ensure that the final target journal matches the
novelty, impact, and interest of the article. The final target journal
does not have to be selected during the kick-off meeting, but a
discussion will help focus the selection.
February 2017
l
37
Kick-off
meeting
Problem
statement
& outline
First draft &
review
Additional
drafts &
reviews
Final draft
Quality
control
Author
approval
Submission
Figure 2: Recommended workflow for preparing an article for submission
Discuss Who Will Be the Authors
The kick-off meeting is also an opportunity to discuss who will
be authors and who will therefore be required to participate
in writing, reviewing, editing, and approving the article.
An experienced writer will be able to advise the team about
who qualifies to be an author and who should instead be
mentioned in the acknowledgments. The main guidelines
for authorship are the International Committee for Medical
Journal Editors (ICMJE) Recommendations (3), which state
that all authors must have:
• Contributed substantially to conceiving or designing the work,
or to acquiring, analysing, or interpreting the data; AND
• Written or edited the article or provided critical comments; AND
• Approved the final version of the article to be published; AND
•A
greed to ensure that questions related to the accuracy
or integrity of any part of the work are appropriately
investigated and resolved
These requirements mean that all authors need to be available
to participate in preparing the article. As with selecting the
journal, a final decision as to who will be authors does not
need to be made during the kick-off meeting, but the list of
authors should be agreed upon shortly thereafter to avoid
conflicts, ethical issues, and lost time.
Discuss the Workflow and Who Will Be
Involved at Each Step of the Project
Coming up with an organised workflow is an essential part of a
kick-off meeting. This includes deciding who will take on what
role and when during the preparation of the article, as well as
how the article will be reviewed and revised. An effective plan
for completing a publication based on a clinical study is shown
in Figure 2. The writing starts with an outline, which should be
reviewed and edited by the main author(s), usually the lead
investigator(s). Once the outline is approved, the first draft is
generated. At this stage, all co-authors should review the article
and provide comments. This is important for ensuring that they all
agree with the direction. Coming in with comments and changes
at a later stage can create conflict and will result in additional and
unnecessary drafts. Subsequent drafts can be kept to a minimum
by clearly defining who should be involved (co-authors only
38
or others also, such as company management or intellectual
property or compliance officers) and at which stage. To meet
ethical guidelines and journal requirements, the final draft must be
approved by all authors before it can be submitted to the journal.
Writing an Effective Article
An effective article needs to communicate and not just disclose.
Disclosing means simply presenting information, which can
be appropriate for a clinical study report, but not for an article.
Communicating, in contrast, means making a link with the
reader and convincing them of something. This implies that the
article needs to be written so that the reader does not have to
work to find information or grasp what it means.
Creating a Problem Statement to
Clarify the Direction for the Article
After the kick-off meeting, the writer needs to start to
determine exactly what the article will be about. This is not
as simple as it seems, and it goes beyond any declared study
objective. Determining what the article will be about can be
accomplished by coming up with a “problem statement” (4).
A problem statement includes two parts, the first defining
what problem the study was trying to solve and the second
defining what the article does to address the problem.
The problem statement does not need to be written down,
but the writer should have one in mind when beginning
the article. Here are two examples:
• Many candidate HIV vaccines have been developed,
but results in animals have not been predictive of efficacy in
humans. A reliable animal model for predicting the efficacy
of HIV vaccines is needed. In this article, we describe a
murine model of HIV that can be used to test vaccines.
• T-type lymphoblastic lymphoma, which mostly affects
young men, has a poor prognosis. New and more effective
treatment protocols are needed. In this article, we describe
the results of a clinical trial on the efficacy and safety
of a paediatric lymphocytic leukaemia-inspired
treatment protocol.
Introduction
What was the overall problem and why
was it important?
Where are things now?
What is missing?
What specific problem did this study
aim to address?
Introduction
• The overall problem and why it is important
• Current situation
• What is missing
• What this study examined
Methods
How was the
problem solved?
Problem
statement
Methods
• Overall study design and ethics
• Participants
• Materials
• Study conduct and outcome measures
• Individual technical methods
• Statistical methods
Results
What information was
added?
Results
• Population characteristics and flow of
participants during the study
• Results of primary study objective
• Results of secondary study objectives
Discussion
Was the objective of the study met?
Why were the results obtained and how do
they compare to earlier results?
What does the problem look like now?
Discussion
• What this study showed
• Individual detailed results and relationship
to the literature
• Considerations, strengths, and limitations (with rebuttals)
• Conclusions and recommendations
Figure 3: The problem statement and its relationship with different sections of an article
Use Outlining to Keep the Article on Track
An outline is a skeleton to organise thoughts and build
the article around. Creating an outline helps keep the
article from going off on tangents. It also serves as a
starting point for discussing and confirming the intended
content of the article. Creating a good outline saves
a great deal of time later by allowing questions
and problems to be dealt with early in the
writing process.
Create a “Concept” Outline
With a clear problem statement, creating a concept outline is
simple. Start with a list of main bullet points or headings. All
parts of the concept outline – and therefore the article – relate
back to the problem statement (see Figure 3).
For example, the first part of the problem statement becomes
the first half of the introduction, and the second part becomes
the second half of the introduction. Subsequent bullet points
or headings address:
• How the problem was solved
• What findings directly address the problem
• Whether the study resolved the problem
• Why the results were obtained
39
•H
ow they compare with other studies
• What the problem looks like now
Create a “Detailed” Outline by
Adding Details to the Concept Outline
Once a basic outline is created, it can be filled in with details
to create a detailed outline. Each of the bullet points or
headings can be elaborated with the full details that would
be included in a first draft. Unlike a first draft text, however,
the information can be included as bullet points, which,
compared to continuous text, are easier to edit, restructure,
or even substantially rewrite.
Carefully Choose the Target Journal
Choosing the target journal early – before starting the first
draft – saves a great deal of time by avoiding the need to
edit, reformat, or substantially rewrite the article to meet the
journal’s requirements. For example, if the “final” draft is 5,000
words long but the journal only allows 3,000 words, substantial
rewriting would be needed, not to mention additional cycles of
review and revision, all of which will add to the time and cost to
complete the project.
Start with Searches of JANE and PubMed
Selecting the right target journal deserves careful thought
and an organised process (see Figure 4). Start by looking
where similar articles are published with keyword searches
on PubMed (5) and BioSemantics Research's Journal/Author
Name Estimator (JANE) (6). A PubMed search will identify
related individual articles, while JANE will identify journals
publishing related articles and will list them in order of
relevance. Neither PubMed nor JANE is perfect, so after
excluding irrelevant journals, combine the results of both
searches to come up with a shortlist of the best options.
Consider the Journal’s Reputation
Next, consider the journal’s reputation. Ask experts and
consider the impact factor, which is a measure of how often a
journal’s articles are cited. Most authors will reflexively want to
target the journal with the highest impact factor, but beware
– the higher the impact factor, the greater the importance
of novelty and the higher the rejection rate. Journals with
higher impact factors also tend to take more time for peer
review. Therefore, carefully – and honestly – assess the article’s
novelty and potential influence. Consider also whether the
objective is to simply publish in a peer-reviewed journal or to
make a big impact.
Other Important Considerations
and Making the Final Decision
Other things to consider include the number of words and
figures/tables allowed, whether supplementary information is
allowed, the journal’s scope, and, if important, whether open
access is available. The final decision should be made by the
full team, but remind them that choosing the wrong journal
will only delay publication and increase the cost.
40
Subject: Results of a phase 3 randomised trial on the efficacy and safety of
an antibody-based biologic for treating rheumatoid arthritis
Novelty & importance: moderate
Key word search:
rheumatoid arthritis, phase 3, randomised clinical trial, antibody
Top relevant journals from
PubMed search
• Arthritis Research & Therapy
(6 articles)
• Journal of Rheumatology
(2 articles)
• Arthritis & Rheumatology
(2 articles)
Top three
target journals
Top journals from JANE search
• Journal of Rheumatology
• Arthritis & Rheumatology
• Arthritis Research & Therapy
• Journal of Clinical Rheumatology
Impact factor
Limitations on length
Arthritis Research &
Therapy
3.979
None
Journal of
Rheumatology
3.69
3,500 words, 6 tables/
figures, 50 references
Arthritis &
Rheumatology
8.955
4,200 words, 6 tables/
figures, 50 references
Final selection: Arthritis Research & Therapy
Rationale: Article’s importance (moderate) matched with impact factor;
journal frequently publishes related articles
Figure 4: The journal selection process
Write the First Draft:
Communicate with the Reader
With a detailed outline in place, creating a first draft is easy.
Simply connect the different points into continuous text. Keep
in mind that the goal of an article is to communicate, that is, to
convince the reader of something. Communicating effectively
requires writing that a reader can easily understand and
process. This can be achieved by avoiding complex, technicalsounding language and aiming for a clear and concise – yet
complete – text. This does not mean talking down to the
reader or avoiding all technical language but rather using plain
language whenever possible and avoiding certain grammatical
constructions that lead to complicated sentences. Also, use
abbreviations sparingly. This avoids frustrating readers by
making them repeatedly look back for definitions. Instead,
reserve abbreviations for complex or multi-word terms that
appear several times. A summary of key points to clarify and
simplify writing is provided in Table 1.
Ensure that All Necessary Information Is
Included in the Article and Is in the Right Place
GPP states that the design and results of clinical studies
should be reported in a complete, accurate, balanced,
and transparent manner. Many guidelines are available
Method
Explanation
Example
Eliminate nominalisations
Nominalisations are verbs turned
into nouns. These almost always
create complicated sentences.
Measurement of concentration was made by ELISA
Improved: The concentration was measured by ELISA
Avoid phrases and
sentences starting with ‘it
is’ or ‘there are’
These create complicated sentences
In patients treated with ibuprofen, there was a much earlier onset of pain relief
Improved: In patients treated with ibuprofen, onset of pain relief was much earlier
Eliminate useless words
Useless words distract from the
sentence’s message
It is well known that fear of needles reduces vaccine uptake
Improved: Fear of needles reduces vaccine uptake
Eliminate ‘respectively’
Using ‘respectively’ tires readers by
making them look backwards
The value was 1, 13, 27 and 54 in groups A, CD, A+CD and A-CD, respectively
Improved: The value was 1 in group A, 13 in group CD, 27 in group A+CD and 54
in group A-CD
Use parallel structure
Parallel structure means using the
same grammatical construction for
items in a list
The time to treatment failure was 12.2 months in the group treated with drug X,
and in the placebo group it was 3.1 months
Improved: The time to treatment failure was 12.2 months in the drug X group and 3.1
months in the placebo group
Avoid multiple hedges
Hedges are ways to avoid saying
anything definite. One is enough.
These results suggest the possibility that drug A might be more effective than drug B
Improved: These results suggest that drug A is more effective than drug B
Keep your subject and
verb close together and
where the reader expects
to find them
The reader may become confused
if they have to hunt for the subject
and verb
A critical gene [subject] that serves as a beacon and gives cells a much-needed sense of
direction in the chaotic days of early development has been identified [verb] by Howard
Hughes Medical Institute (HHMI) researchers
Improved: HHMI researchers [subject] have identified [verb] a critical gene that gives cells a
much needed sense of direction in the chaotic days of early development
Table 1: Methods for simplifying writing
to help authors accomplish this. Key guidelines include
CONSORT for randomised controlled trials, TREND for
non-randomised trials, STROBE for observational studies,
and CARE for case reports (see Table 2). A comprehensive
and searchable database of guidelines for reporting
clinical studies can be found on the EQUATOR
Network website (7).
Reporting guidelines typically include checklists of
the items that need to be included in each section of
an article. Also included are detailed explanations for
how to complete each item. Thus, reporting guidelines
are excellent resources for planning and producing
publications. Authors should be aware that most journals
now require that the relevant reporting guideline is
Publication type
followed and, in some cases, that the completed checklist is
submitted along with the manuscript.
Write the Abstract Last
Take a close look at the journal’s instructions for authors because the
journal will not accept an abstract that is over their stated word limit.
The instructions for authors may also have specific requirements
for the structure and content of the abstract. In addition, use the
CONSORT Extension for Abstracts as a checklist to make sure that
the abstract is complete (8). If you are not reporting a randomised
controlled trial, simply ignore any irrelevant items in the checklist.
As most readers will see only the abstract, a reader must be able
to understand it without needing to read the main text. To write a
Reporting guideline
Website
Randomised controlled trials
CONSORT
www.consort-statement.org
Non-randomised trials
TREND (or CONSORT*)
www.cdc.gov/trendstatement
Observational studies
STROBE
www.strobe-statement.org/index.php?id=strobe-home
Case reports
CARE
www.care-statement.org
Qualitative studies
COREQ
www.intqhc.oxfordjournals.org/content/19/6/349.long
Diagnostic/prognostic studies
STARD, TRIPOD
www.equator-network.org/reporting-guidelines/stard
www.tripod-statement.org/tripod/tripod-checklists
Systematic reviews and meta-analyses
PRISMA
www.prisma-statement.org
Meta-analyses of observational studies
MOOSE
www.statswrite.eu/pdf/MOOSE%20Statement.pdf
*CONSORT can be adapted to non-randomised trials by excluding any non-relevant items
Table 2: Types of clinical publications and their associated reporting guidelines
41
stand-alone abstract, begin with the main study objective. State
the objective clearly in one sentence, removing all extraneous
words. Next, state the conclusions in one sentence. Be sure that the
conclusions directly reflect the main study objective. Next, add only
the results that support the conclusions and then only the methods
that support the included results. Add one sentence of background
to complete the abstract. If any words are left, additional interesting
results (and supporting methods) can be added.
Review, Revise, and Quality Control
The writer needs to work with the authors and other team
members during the planned review cycles to prepare
subsequent drafts and, eventually, the final draft. To avoid
complications and confusion, stick to the process that was
established during the kick-off meeting. Also, avoid moving
forward with subsequent drafts until all participants have
provided the necessary input. If essential contributors are not
providing timely comments, it may be necessary to remind them
that they need to participate to be listed as a by-line author.
As a final step before requesting author approval of the final
version of the article, perform quality control to make sure it
is free of errors. The quality control should include, at
a minimum, checks of the following:
• Spelling, grammar, and punctuation
• Consistency of data/numbers between source information (eg
clinical study reports), figures, tables, main text, and abstract
• References
• Formatting according to the instructions for authors
•C
ontent according to the relevant reporting guideline
(eg CONSORT)
Submitting the Article to the Journal
authors. Some online submission systems ask for unexpected
details that can take time to collect, such as highest degrees
for all authors, copyright permission and transfer forms,
detailed authorship contribution statements, lists of reviewers
to recommend or exclude, and permission letters from people
to be acknowledged. To avoid surprises, explore the online
submission system in advance.
Dealing with the Editor’s Decision:
Revising and Resubmitting
After receiving the article, if all goes well, the editor will send
it out for review. Many articles, however, are rejected without
review. If this happens, do not waste time contacting the
editorial office to ask them to reconsider. Instead, prepare to
send it to a new, perhaps more carefully selected, target journal.
Most articles that make it into peer review will not be
accepted immediately but will instead come back with many
comments and questions. Usually, the editor will indicate that
the article will be reconsidered if the comments and questions
are addressed, but in some cases the editor will reject the
article with no chance for resubmission after a full review.
In either case, consider the comments carefully. Put aside
any negative emotions, and think about the comments from
the reviewer’s point of view. If the reviewer misunderstood
something, it probably means that that part of the article
was not clear enough. Consider also that the comments
are of great value: they are expert opinion, and they are an
opportunity to improve the article. For an article that has been
Dear Editor,
I would like to submit our manuscript “1-year follow-up of safety of drug
Write a Cover Letter that Convinces
the Editor to Review the Article
Once the article is complete, prepare a cover letter to be
submitted with the article. The cover letter is a chance to catch
the editor’s attention and convince them that the article should
be published in their journal. It should briefly explain the purpose
of the letter, summarise the purpose and findings of the article,
and include a statement on the article’s relevance to the journal
and a short thank-you (see Figure 5). Refer to the instructions for
authors to see if any additional information is needed. Be careful
not to let the cover letter get too long: to avoid overwhelming
the editor, it should not be longer than one page. Also, do not put
any pressure on the editor to review or accept the article.
Plan Enough Time to Submit the Article
Plan a full day to submit the article. Although this might
seem like a lot of time, it is often necessary because online
submission systems can be tedious and time-consuming.
Start by collecting the article and cover letter, the figures
(prepared in the appropriate format and resolution), conflict
of interest forms, and detailed contact information for all
42
X in patients with ankylosing spondylitis” for publication as a research
article in Joint Research and Therapy. [Introduction]
The manuscript describes the results of a prospective, multi-centre,
open-label observational study on the safety of drug X in patients with
ankylosing spondylitis. This 1-year systematic safety survey provides
important, detailed information about adverse events, predictors for
adverse events and reasons for discontinuation in daily clinical practice.
[Short summary]
We feel that this is important information and directly relevant to the
readership of Joint Research and Therapy, particularly in the context of drug
safety in the rheumatic diseases. [Statement of relevance]
Thank you for considering our manuscript for publication. We look
forward to your response. [Thank-you]
Sincerely,
Professor John Johnson
Department of Rheumatology
Central Wyoming College of Medicine
Figure 5: Example cover letter
Comments numbered
Where in the text the
changes can be found
RESPONSE TO REVIEWERS’ COMMENTS
Reviewer #1 Comments
1. The term 'day 28/56' is confusing. Use just 'day 56',
which will be clear that the sample was taken on day
56 of the study, i.e., 28 days.
We changed this to “28 days post-vaccination” throughout the
manuscript.
2. Present an analysis of non-inferiority (Table 2) in the full data set
- given that the differences between the two samples are too large,
in particular in group A.
To include this information, we modified the text as shown below
(page 10, line 27; new text underlined) and added a supplemental
table:
Formatted to help the
reader find the comments
and responses
Detailed response with
what was done and why
Professional tone
The primary objective of non-inferiority of vaccine 1 vs.
vaccine 2, analysed in the per-protocol population, was met
for all vaccine strains as indicated by a lower limit of the twosided 95% confidence interval for the ratio of the geometric
mean antibody concentrations of >0.667. Results were
similar when the analysis was performed in all randomised
subjects (Supplemental Table S1).
Modified text with changes indicated
Figure 6: Excerpt from an example response document
rejected, revising it according to the comments can greatly
improve its chances of being accepted by a new journal.
4. H
urley M, What’s your problem? A practical approach to scientific
document design, Medical Writing 21(3): pp201-204, 2012
5. Visit: www.ncbi.nlm.nih.gov/pubmed
If the editor has offered you the opportunity to resubmit
the article following revision, they will ask for point-by-point
responses to the reviewers’ comments. When responding,
maintain a professional tone and provide the reviewers with
any information that can help answer their question or address
their comment. If two reviewers contradict each other, try to
find a way to satisfy them both. If necessary, seek guidance
from the editor. If it is impossible to do something requested
by a reviewer, explain why. Finally, a well-formatted response
document, such as the one shown in Figure 6, will be much
appreciated by the editor and reviewers and will increase the
likelihood that the article is accepted for publication.
Conclusion
Publication in a peer-reviewed journal is now required for all
clinical studies, except for the few studies that do not provide
meaningful data. This ensures a robust base of evidence to inform
clinical decisions. To be effective, an article needs to communicate,
which means making a link with the reader and convincing them
of something. Keys to success include establishing and following
an organised process for producing the article, selecting the right
journal, following relevant guidelines, and making life easy for the
reader, editor, and reviewers.
References
1. Wager E et al, Good publication practice for pharmaceutical companies,
Curr Med Res Opin 19(3): pp149-154, 2003
6. Visit: http://jane.biosemantics.org
7. Visit: www.equator-network.org
8. H
opewell S et al, CONSORT for reporting randomized controlled trials in
journal and conference abstracts: Explanation and elaboration, PLoS Med
5(1): e20, 2008
About the authors
Phillip S Leventhal, PhD, is a Scientific
Writer at 4Clinics, where he specialises
in publications. He also is the Editorin-Chief of the journal Medical Writing,
leads workshops in Europe and the US
on scientific writing, and is an Adjunct
Associate Professor in the professional writing programme
at New York University.
Email: [email protected]
Stephen Gilliver, PhD, is a Medical
Writer at TFS in Lund, Sweden, where
he writes publications, clinical study
protocols, and clinical study reports. He
is the Co-Editor of Medical Writing and
occasionally teaches scientific writing. He
was previously employed for four years as a science editor,
primarily working with researchers to improve
their manuscripts.
2. Battisti WP et al, Good Publication Practice for communicating companysponsored medical research: GPP3, Ann Intern Med 163(6): pp461-464, 2015
Email: [email protected]
3. Visit: www.icmje.org/recommendations
43
Medical Writing: The Backbone of Clinical Development
Medical Publication
Managers: Are Your
Publications FutureProof and Audit-Proof?
Medical publication managers are faced with the challenge of getting
the results of clinical research out to targeted health professionals in an
effective, efficient and compliant manner. This article describes tools,
techniques and technology to help achieve this.
“What you do today can improve all your tomorrows”
Ralph Marston
High-performing publication managers in the pharmaceutical
industry consistently facilitate the delivery of compelling,
credible, and compliant publications. How?
By Professor Karen
L Woolley and Dr Mark J
Woolley at Envision
Pharma Group
Firstly, they are leaders, not laggards. To help future-proof
their publications in an environment that is continually
evolving, they embrace innovation. They know they need
to adapt their publication plans and practices or risk
being left behind.
Social media
insights
Shared data
reanalyses
Peer reviewers
Co-authors
Advisory board
Publication
steering committee
Co-presenters
Carer-reported
outcomes
Electronic health
record analyses
Patient-reported
outcomes
Prescription
database analyses
‘Patient involvement
statement’ to be
included in
publication
Digital landscape
analyses
of 2,346
respondents from
84 countries believe
patient-centricity
improves
business
The Aurora Project 2016
Online
advisory boards
Digital offerings
(journals & congresses)
Metrics
Video
abstracts
Interactive
posters
Infographics
are shared on
social media
more than any
other type of
content
Use of
information
correlates with
scientific
impact
Analysis of 650,000+
papers on PubMed, 2016
Global Publication Survey, BMJ Open 2014
Figure 1: Four trends publication managers can leverage to future-proof and audit-proof their publications.
All publications should be developed ethically, with the ultimate goal of enhancing patient outcomes
44
l
February 2017
of pharma clients
use a publication
management tool
for compliance
Secondly, they are audit-ready, not audit-averse.
To help audit-proof their publications, particularly when
transparency is critical to building trust, they embrace
technology. They know they can leverage technology
to transparently track and document compliance −
globally, efficiently, and effectively.
The purpose of this article is to help publication managers
become high-performing publication managers. To help
managers future-proof their publications, we identify four
trends affecting the publication environment and provide
practical guidance on how to leverage these trends to deliver
compelling and credible publications. To help managers
audit-proof their publications, we share real world insights
on how to use publication management software
to transparently track and deliver compliant publications.
How to Future-Proof your Publications
“The best way to predict the future is to create it”
publication management software (eg Datavision®) to help
authors – be they patients or healthcare professionals – to
select journals and congresses that strive to include patients
as partners. We are currently conducting research on how
well journals and congresses are performing on this metric,
based on predetermined criteria established by
patient advocates.
High-performing publication managers recognise the
importance of patient engagement, but also understand the
need to respect patient diversity − not all patients want to be
publication partners, not all patients want to immerse themselves
in the peer-reviewed literature. However, to deny or ignore
those who do robs medical research of the insights necessary to
truly enhance patient outcomes. Assumptions about patients
and publications are being challenged by research, including
studies that we have conducted on patient acknowledgements
in publications, on consumer preferences for sharing research
results, and how the public around the world engages with
the peer-reviewed literature via social media (1-3).
Peter Drucker
Publication managers can help future-proof their publications
by identifying and responding to important trends in the
publication environment. There are many changes affecting
publications, but we will focus on four major trends
(see Figure 1).
Patients as Publication Partners
Clearly, patients are not new; they are the raison d’être for
publishing medical research. What is new is the increasing
recognition that patients, as well as carers and the public,
can be publication partners (see Figure 1). This is a change
that publication managers can and should embrace, and
champion among their internal and external stakeholders.
Patients can be authors, presenters, and peer-reviewers.
Patients can offer ‘end user’, first-hand, expert insights
through appointments to Advisory Boards (eg providing
insights on unmet needs and research protocols) and
Publication Steering Committees (eg providing insights
on how, when, and where to present and publish research
results). Notably, more journals are embracing patientcentric publications, and publication managers can use
This research has established that publication managers are wellpositioned to be change agents in the drive to engage patients
as publication partners. Publication managers can bring patients,
researchers, and sponsors together to develop publication plans
and outputs that meet the educational needs of patients. Further,
in our interactions with inspiring and pioneering patients and
advocacy organisations around the world (eg the International
Alliance of Patients’ Organizations, the Patient Innovation
Platform, the Advocacy Service for Rare and Intractable Diseases,
Genetic Alliance Australia) there has been genuine interest, if not
optimistic impatience, about the role that patients should have
in publication planning and delivery.
In practical terms, we acknowledge that concerns may be raised
about the costs and compliance issues of engaging patients
as publication partners, particularly for industry-sponsored
publications. It would be naïve to assert that publication
managers should not consider such costs, even if they believe
patient engagement is the right thing to do. We are not aware
of any empirical research on the return on investment of
engaging patients as publication partners. We note, however,
that results from the Aurora Project survey (conducted in March
2016; N = 2,346 respondents from 84 countries) showed that
Patients can be authors, presenters, and peer-reviewers.
Patients can offer ‘end user’, first-hand, expert insights through
appointments to Advisory Boards (eg providing insights on unmet
needs and research protocols) and Publication Steering Committees
(eg providing insights on how, when, and where to present and
publish research results)
45
Japan is the 2nd largest
pharma market in the world
trials
trials in Japan:
publications
2-3x more than the US or EU*
Change in industry-sponsored Phase 3 trials (2011-2015)
*ISMPP 2016 Best Original Research Prize to Envision
Medical Affairs staff in Asia* manage publications
but <1 in 10 has strong knowledge of ethical and
effective publication practices
* Envision research (>100 Medical Affairs staff in Asia including Japan)
Figure 2: Publication managers need to ensure their publications are audit-ready, globally. This is especially true in
countries like Japan, which a) is a key market, b) is increasing its industry-sponsored clinical trial activity, and c) has limited
staff with expert knowledge and experience of GPP
93% of respondents believed that patient-centricity improves
business outcomes, including enhancing patient outcomes
and trust (4). Engaging patients as publication partners could
help drive these positive outcomes and justify the incremental
investments made to do so.
In terms of compliance, changing publication practices
will, and arguably should, raise questions about the right
way to proceed. Minimal guidance is provided in the Good
Publication Practice (GPP) 3 guidelines (5). Publication managers
can, however, refer to general and publication-specific
recommendations from other sources, including:
• The Consensus Framework for Ethical Collaboration between
Patients’ Organisations, Healthcare Professionals and the
Pharmaceutical Industry (6)
• The Guidance for Reporting Involvement of Patients and Public
(GRIPP) checklist (7); GRIPP 2 is under development
• Journal guidance on involving patients in publications (eg
recommendations from The British Medical Journal (BMJ)) (8)
Content beyond Clinical Trial Data
With the regulatory requirements for clinical trials, the core of
many publication plans consists of clinical trial publications.
However, given the time, cost, and complexity of clinical trials,
as well as their imperfect reflection of the real world, these
publications do not address all unmet needs. Additional sources
of content can provide credible, yet quicker and cheaper
answers to real world questions and complement findings
from clinical trials.
Publication managers can work with internal and external
stakeholders to identify unmet needs that can be legitimately
addressed by generating and sharing content outside clinical
trials (see Figure 1). For example, we have worked with
clients and our own research teams to analyse, present, and
publish content from patient- and carer-reported outcomes,
46
administrative claims and prescription databases, shared data
re-analyses, and social media insights (3, 9-11).
Visuals
Scientists have long recognised the value of graphics as an
educational tool, but have been slower than other professionals
to fully appreciate the value of infographics and other visual
storytelling tools. Although the traditional conservatism of
science may have hindered the rapid uptake of these tools,
the visual trend is now gaining ground (see Figure 1).
Industry associations (eg the International Federation of
Pharmaceutical Manufacturers & Associations, European
Federation of Pharmaceutical Industries and Associations,
Pharmaceutical Research and Manufacturers of America),
medical journals (eg The BMJ), and regulators (eg the EMA, FDA)
are publishing their own infographics, providing strong signals
to scientists that creativity and credibility can coexist. Increasing
research on visual communication tools and the emerging
science of viziometrics are also providing empirical evidence
on the use and value of visuals in research publications (12-15).
Unless authors fully engage their readers, they cannot educate
them. High-performing publication managers can help
authors access the resources needed to develop engaging,
creative, and credible visuals. These visuals focus on the
needs and preferences of the relevant target audience. In our
world of information overload, visually appealing graphics
can help attract and retain reader attention. Not surprisingly,
medical journals have started to encourage authors to submit
infographic-style abstracts. Publication managers are wellpositioned to guide authors on how to develop infographics
that may enhance efficient and effective comprehension
and retention of complex ideas.
Technology
Technological advances offer high-performing publication
Audit risk
Datavision feature
Compliance solution
Noncompliance with company policies and
procedures and publication guidelines
(eg ICMJE, GPP3)
Authorship agreements can be tracked,
documented, and archived per company
requirements
Able to ensure authors understand the need to
comply with the company’s requirements
before the project begins; able to access and
use agreements to reinforce the need for
compliance during the project
Lack of author access to data
Study-related documents can be stored
and shared; authors can have direct access
during the project
Able to show that authors are able to access
the information they need to fulfil their
authorship responsibilities
Guest authorship
Author input can be tracked,
documented, and archived
Authorship eligibility can be proven based on
documented compliance with internationally
recognised criteria
Ghostwriting
Author and writer input, as well as all drafts, can
be tracked, documented, and archived
Early, continual and appropriate author input,
as well as legitimate contributions from the
writer can be proven based on a review of
input from each on successive versions
of the document
Non-disclosed conflict of interest
Disclosure forms can be distributed, collected,
tracked, and archived
The risk of inconsistent, outdated, or incomplete
disclosures can be reduced. Automation can
reduce the administrative burden, providing
more time for reviewing disclosure content
Non-acknowledgement of contributions
Input and support by non-author contributors can
be tracked. Acknowledgement agreements can be
distributed, collected, tracked, and archived
The risk of incomplete, inappropriate, or
unauthorised acknowledgement can be reduced
Not following reporting standards
(eg CONSORT)
Datavision checklists help ensure documents
can be checked against reporting standards
before submission
The risk of not including information deemed
critical by reporting experts can be reduced
Unjustified publication
Needs assessments can be tracked, documented,
and archived. Datavision also allows the entire
plan to be visualised
The rationale for each publication can be
verified efficiently and effectively. The risk of
duplicate publications can be minimised (ie
duplicates can be readily detected from a visual
overview of the plan)
Unjustified choice of conference or journal
The Datavision Journal and Conference database
lists legitimate journals and metrics. Authors’
choices can be documented and archived
Rationale for authors’ choices can be retrieved
and metrics used to support those choices can
be identified. Comprehensive and regularly
updated lists can help minimise the risk of
selecting predator journals and conferences
Table 1: Examples of Datavision features that can help publication managers become audit-ready
managers new ways to enhance publication planning,
delivery, and compliance (see Figure 1). Digital platforms
and social media analytics can help publication planners
develop and evaluate strategies that address real world issues.
Publication managers and their stakeholders do not have to
wait for years to determine the impact of an publication –
technology now allows them to quantify who engaged with
their publications, when, where, and how this engagement
took place, and how positive (or negative) these reactions
were to the published research.
Technology can also help publication planners enhance the
speed, novelty, and geographic reach of their publication
tactics. We have worked with clients and authors in Europe,
North America, and the Asia-Pacific region to deliver timely,
durable, and high-quality digital publications (eg video
abstracts and interactive posters) that can be accessed
simply and freely, in English or local languages. Technology
can also be used to help authors identify journals and
congresses that have embraced these innovative digital
delivery methods. For example, publication management
software, such as Datavision, which is used as both a project
management and compliance tool (see Table 1), has a
Journal and Congress database that managers can use to
efficiently check which, of the more than 27,000 journals and
congresses listed, offer digital options. Given the evolving
publication environment and rapid advances in technology,
developers of publication management software should
consult regularly with their end user community and
dedicate the resources required to ensure software
updates meet the needs of this community.
How to Audit-Proof your Publications
“Remember that even if you haven't been audited in
the past, it doesn't mean you won't be in the future.
And it only takes one audit to ruin your day”
Kathy Burlison
To help build trust in industry-sponsored publications,
publication managers should ensure compliance with
company policies and procedures. Compliance should be
transparent and global. This may be ‘easier said than done’,
but auditors want to know what was done and will ask for
the documentation to prove it. That is why high-performing
publication managers want to be audit-ready. They know
that compliance and audit readiness can be influenced by
both people and technology.
47
Increasing number of Datavision clients
62
54
45
41
31
27
24
20
18
12
10
6
1
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
Figure 3: The use of publication management software (eg Datavision), as both a publication management and compliance tool,
is continually increasing in terms of its global reach (eg Japan is now one of the top 10 countries using Datavision) and client base
(eg Datavision is licensed by more than 30 of the world’s top 50 biopharmaceutical companies and used by more than 150 medical
communication companies; there are more than 115,000 registered Datavision users worldwide)
In terms of people, we and others have shown that people’s
knowledge can influence compliance (11,16). For example,
publication professionals who have proven their knowledge (ie
have passed an exam at an independent, secure, testing facility) to
become certified medical publication professionals are more likely
to have broader and more current knowledge than those without
this credential (11). Professionals with stronger knowledge are also
more likely to comply with ethical publication practices (16).
Importantly, audit readiness must be global. High-performing
publication managers provide the resources necessary to
manage audit risks, particularly in major markets. For example,
Japan is a key market and is experiencing a surge in industrysponsored clinical trials (see Figure 2). Compared with other
key markets, however, Japan and the wider Asia-Pacific region
have relatively few experienced and certified publication
professionals. Medical Affairs staff typically have responsibility
for publications and, although their knowledge of GPP and
other publication-specific guidelines is increasing, strong
Medical Affairs staff typically have responsibility for publications
and, although their knowledge of GPP and other publication-specific
guidelines is increasing, strong support may be required to ensure audit
readiness. The need for additional resources is likely to intensify as more
internationally focused Japanese pharma companies take responsibility
for global publication plans
48
support may be required to ensure audit readiness. The need for
additional resources is likely to intensify as more internationally
focused Japanese pharma companies take responsibility for
global publication plans. Notably, in some organisations,
the transfer of global publication planning from US teams to
Japanese teams has already occurred.
10. Campbell JC et al, Patient adherence and persistence with topical ocular
hypotensive therapy in real-world practice: A comparison of bimatoprost
0.01% and travoprost Z 0.004% ophthalmic solutions, Clin Ophthalmol 8:
pp927-935, 2014
11. Woolley KL et al, The Certified Medical Publication Professional (CMPP)
credential: More than a knowledge test?, Curr Med Res Opin 31: S8, 2015
12. Turck CJ et al, A preliminary study of healthcare professionals’ for
In terms of technology, one of the largest surveys of publication
professionals (conducted in November 2015; N = 469
respondents from 23 countries) highlighted how publication
management software is now being used not only as a planning
tool, but also an audit tool (17). Of the agency respondents,
94% reported that their pharma clients used such software to
assess compliance. Consistent with this finding is the global
growth in the use of publication management software, such
as Datavision (see Figure 3), which can help clients and agency
staff be audit-ready (see Table 1) (18).
infographics versus conventional abstracts for communicating the results
of clinical research, J Contin Educ Health Prof 34: S36-38, 2014
13. Crick K and Hartling L, Preferences of knowledge users for two formats
of summarizing results from systematic reviews: Infographics and critical
appraisals, PLoS ONE 10: e0140029, 2015
14. Scott H et al, Why healthcare professionals should know a little about
infographics, Br J Sports Med 50: pp1,104-1,105
15. Lee PS et al, Viziometrics: Analyzing visual information in the scientific
literature, arXiv: 1605.04951, 2016
16. Hamilton CW and Jacobs A, Ghostwriting prevalence among AMWA and
EMWA members (2005 to 2014), Medical Writing 25: pp6-14, 2016
In summary, high-performing publication managers are
catalysts for advancing the publication profession. They
embrace new trends in a judicious and compliant manner.
They know that in a rapidly evolving environment, they need
to adapt their practices or risk being left behind. Because
they are leaders, not laggards, they are proactively leveraging
trends and technology. At all times, however, they base
their actions on ethical principles and focus their actions
on improving patient outcomes. Publication managers can
become high-performing publication managers if they work
with their stakeholders to ensure their publications are,
indeed, future-proof and audit-proof.
Acknowledgements
We thank our Envision colleagues for their professional support
(Graphic designers: Greg Flocco from the US and Evelyn Lee
from Australia; Editor: Vivia Beinart from Australia; Technology
Solutions – Datavision: Rus Traynor from the UK).
References
1. B
hatia R and Anthony B, Clinical trials: Do patients get the thanks they
deserve?, Curr Med Res Opin 31: S19, 2015
2. K
eys JR et al, Sharing results with clinical trial participants: Insights from an
17. Wager E et al, Awareness and enforcement of guidelines for publishing
industry-sponsored medical research among publication professionals:
The Global Publication Survey, BMJ Open 4: e004780, 2014
18. Traynor R and Gegeny T, DatavisionTM – What do medical writers need to
know?, Medical Writing 23: pp29-35, 2014
About the authors
Professor Karen L Woolley is Director
of Global Strategic Initiatives – Medical
Affairs at Envision Pharma Group in
Tokyo, Japan. She has more than 25
years of publication and clinical research
experience, and has worked in academia,
industry, and agency settings. Karen is also an Adjunct
Professor at two Universities, a government-appointed
director of a large ($1B) hospital and health service, is a
Life Member of ARCS, an Honorary Fellow of the American
Medical Writers Association, has served on the International
Society for Medical Publication Professionals (ISMPP)
Board, and was the inaugural Chair of the ISMPP Asia
Pacific Advisory Committee.
online survey of Chinese consumers, Chin Med J 129: pp1,007-1,008, 2016
3. Woolley KL et al, Who engages with patient-centered, peer-reviewed
Email: [email protected]
publications? Tweeting of JAMA Patient Pages, Curr Med Res Opin 32: S14, 2016
4. Visit: http://social.eyeforpharma.com/commercial/shining-light-patientfocused-profitability
5. Battisti WP et al, International society for medical publication professionals,
Good publication practice for communicating company-sponsored medical
research: GPP3, Ann Intern Med 163: pp461-464, 2015
6. Visit: www.iapo.org.uk/consensus-framework-ethical-collaboration
7. S taniszewska S et al, The GRIPP checklist: Strengthening the quality of
patient and public involvement reporting in research, Int J Tech Assess
Health Care 27: pp391-399, 2011
8. Visit: www.bmj.com/about-bmj/resources-authors/article-types/research
9. C
hancellor M et al, OnabotulinumtoxinA improves health-related quality
of life in patients with urinary incontinence due to neurogenic detrusor
overactivity, Neurology 81: pp841-848, 2013
Dr Mark J Woolley is Director, Global
Strategic Initiatives – Technology at
Envision Pharma Group. Mark has more
than 25 years of publication and clinical
research experience, and has worked in
academia, industry, and agency settings.
He co-founded ProScribe Medical Communications in 2000,
which was sold to Envision Pharma Group in 2014. Mark
is working with his global colleagues at Envision to support
service and software users, particularly those in the AsiaPacific region.
Email: [email protected]
49
Medical Writing: The Backbone of Clinical Development
The Pharmacovigilance Medical
Writer: Medical Writer, Project
Manager, Regulatory Expert
Pharmacovigilance is a critical element of drug development and marketing.
The evaluation and monitoring of patient safety and a drug’s benefit/risk is
a highly regulated global task, which is required continuously throughout
a drug’s lifecycle. The results of such analyses are reported to health
authorities in periodic aggregate reports, and further PV documentation
such as the RMP are increasingly required in regulations worldwide.
The pharmacovigilance (PV) medical writer plays a crucial
role – not only in the production of these documents, but also
in their management. A skilled PV medical writer provides PV
expertise; extensive knowledge of formal requirements and
guidelines; document, format, and content expertise; and writing,
communication, and project management skills. These skills
ensure that the presentation of patient safety, the drug’s benefit/
risk profile and the company’s risk management assessments to
regulatory authorities are clear and consistent across the whole
suite of PV documents, and that these documents are produced
in a timely and efficient manner.
Introduction
Throughout clinical development and the post marketing
phase, drug developers and marketing authorisation
By Sven Schirp at
Boehringer Ingelheim
and Lisa Chamberlain
James at Trilogy Writing
& Consulting
holders (MAHs) invest heavily in monitoring and evaluating
patient safety, and in managing the risks associated with
drug exposure. The term “pharmacovigilance” encompasses
the science and activities relating to the surveillance,
detection, assessment, understanding, and prevention
of adverse effects or any other drug related problem.
Surveillance of safety data is a permanent activity, designed
to ensure that potential safety signals are detected early
and that the risks of exposing a patient to adverse
drug effects are minimised.
Safety data are then analysed and the results provided to
regulatory authorities (RAs) in periodic aggregate reports, most
notably the Development Safety Update Report (DSUR) and
the Periodic Benefit Risk Evaluation Report (PBRER or PSUR).
The MAH has a legal obligation to assess and manage the risks
NG
KETI
-MAR
POST
L
VA
RO
P
AP
(DSUR/RMP update)
PBRER
RMP
EL
OP
M
EN
T
Produced as needed
DE
V
GVP module V
Rev. 2
DSUR
Annual from
DIBD
Whenever trials
are being conducted
ICH E2F
Figure 1: PV documents in the drug’s lifecycle
50
l
February 2017
• Interval of <12 months:
70 calendar days after DLP
• Interval of >12 months:
90 calendar days after DLP
• Ad hoc: usually within
90 calendar days of request
ICH E2C(R2)
GVP Module VII
IMPLEMENT
risk minimisation
/characterisation
and benefit
maximisation
SELECT & PLAN
risk characterisation
/minimisation and
benefit
maximisation
techniques
DATA COLLECTION
monitor effectiveness
and collect new data
RISK MANAGEMENT
CYCLE
IDENTIFY & ANALYSE
risk quantification
and benefit
assessment
EVALUATE
Benefit-risk balance
and opportunities to
increase and/or
characterise
Source: GVP Module V Rev 1
Figure 2: The risk management cycle
associated with their drug, and their risk management system
and its associated risk minimisation activities are documented
in the Risk Management Plan (RMP). Each of these documents
is required at a different stage of a drug’s lifecycle and fulfils
different roles (see Figure 1).
Traditionally, PV documents have been authored by experts from
the main contributing disciplines, eg PV, regulatory affairs, and
medical affairs. However, implementation of the EU Guideline
on Good Pharmacovigilance Practices (GVP) in 2012 introduced
extensive changes, particularly to the format and scope of the
PBRER and RMP, and to the way PV documents are assessed.
To meet the challenge of these changes, the PV medical writer
works in collaboration with the traditional team of authors. The
medical writer’s role is crucial to ensure that the presentation of
patient safety, the drug’s benefit/risk profile, and the MAH’s risk
management assessment are clear to RAs, are consistent across
the whole suite of PV documents, and that PV documents are
produced in accordance with their strict deadlines.
The PV Medical Writer and
the PV Document Lifecycle
DSURs
The requirement to submit PV documents to RAs starts
with the first authorisation to conduct a clinical trial in any
country worldwide. This date is defined as the development
international birth date (DIBD) and marks the beginning of
the reporting period of the first DSUR. The first data lock point
(DLP) is 12 months thereafter and, as defined in ICH E2F along
with their content and format, annual DSURs must then be
submitted for as long as patients are exposed to the drug in
interventional clinical trials. The DSUR must be submitted to
RAs within 60 days after DLP.
The aim of the DSUR is to provide a periodic analysis of the
safety of an investigational drug in clinical trials, to ensure
patient safety during clinical development. There are several
other requirements for reporting individual adverse events
during trials, and so the DSUR is not the primary tool for
51
EU
US*
Japan
Every 6 months for 2 years
Annually for 2 years
Every 3 years afterwards
Every 3 months for 3 years
Annually afterwards
Every 6 months for 2 years
Annually afterwards
*The FDA accepts all three formats, the PADER/PAER, PSUR, and PBRER to fulfil the post-marketing
periodic safety reporting requirements. Timings given here are for the PBRER.
Source: ICH E2C (R2), www.fda.gov
and www.redlinepv.co.uk
(accessed Dec 16)
Table 1: Reporting frequencies of PBRERs
reporting new important safety information to RAs. Instead, it
summarises all relevant safety information that was collected
during the reporting period. As for all PV documents, time can
be a critical issue, and this is especially the case when working
on DSURs for drugs well advanced in clinical development.
The PV medical writer guides the team through the specific
requirements of the DSUR and ensures that the document is
concise and focuses on new and relevant safety information.
DSURs are produced during clinical development, and so the
most critical point is the introduction of “important identified
and important potential risks”. These are well defined subsets
of the risks known to be, or are potentially, associated with the
investigational drug, as described in the Investigator’s Brochure.
An important risk is any risk that could have an impact on the
benefit/risk profile of the drug or have implications for public
health. Once defined in the DSUR, important identified and
potential risks are carried forward beyond marketing approval
and significantly drive the content of other PV documents (eg
the RMP and the PBRER), and may require specific PV activities
to prevent or minimise them. They must therefore be selected
carefully and the PV medical writer’s role and experience is
crucial to guide the team and alert them to the implications for
future documents.
RMPs
In the EU and an increasing number of non EU countries,
an RMP is required for any new marketing application. The
content and format of the RMP is defined in GVP Module V. The
document is well regulated in the EU and is well established
globally. It is provided to RAs in Module 1 of the Common
Technical Document (CTD) submission dossier and is one of
the last documents to be completed before the Marketing
Authorisation Application is submitted because it can only
be finalised when the Summary of Product Characteristics is
final. The aim of the RMP is to describe the safety profile of the
drug, ie the important identified and important potential risks,
plus any missing information (which is usually composed of
potential risks for sub populations that were not sufficiently
investigated in clinical trials).
In addition, the RMP must describe measures to prevent or
minimise these risks and methods to assess the effectiveness
of the interventions. It describes any post authorisation
obligations and evaluates whether the efficacy shown in clinical
studies is also seen in everyday medical practice, and whether
there is a need for post authorisation efficacy trials. To write the
RMP, the PV medical writer must have a sound knowledge of
52
the relevant guidelines and ensure that all contributions from
other authors comply with GVP requirements. In addition, they
must ensure that information contained in other submission
documents (eg CTD clinical summaries) is in line with the data
presented in the RMP.
The PV medical writer also uses his/her expertise and
knowledge of the guidance and requirements to plan the
most appropriate document format and the level of detail for
data presentation, leading discussions on the risks and their
categorisation as safety concerns, and on the strategic planning
of related submission documents.
Risk management is a permanent activity that is ongoing for as
long as patients are exposed to a drug. In this sense, the RMP is
an exceptional document because it can be revised at any time
in the drug’s lifecycle. Starting with version 1 (submitted with the
initial marketing application), the RMP is assessed by RAs and
might then be updated and revised multiple times until the drug
is approved. In the post-marketing phase, the RMP is frequently
updated whenever new safety information becomes available
and in response to specific PV activities (see Figure 2).
RMP management is also an ongoing activity, involving updating
the RMP and implementing or responding to comments from
regulatory assessors. Depending on the level of project activity
(eg submissions for new indications, line extensions), multiple
versions of the RMP can be under assessment simultaneously
by various global RAs. PV medical writers have a central role
in maintaining oversight of the RMPs created for parallel
submissions, managing complicated version control. The content
of the RMPs can also vary between different regions according
to local requirements. These are often complex issues, and good
team interaction and internal processes are crucial.
PBRERs/PSURs
In the ICH regions, creating post marketing PSURs is a prerequisite
of marketing approval. This can be the PBRER in the EU (GVP
module VII) and most Eastern European countries, the Periodic
Adverse Drug Experience Report (PADER) in the US, or the Annual
Safety Report (ASR) in Canada. The PBRER is accepted by most
countries, even those that provide specific local report templates,
and its content and format are specified in ICH E2C (R2).
The reporting requirement and period of the PBRER starts
with the International Birthdate ie, the marketing approval
date. In the EU, the reporting frequency for each drug
is published online in the EU reference date list. After
marketing approval, this frequency varies by region and drug
lifecycle point (see Table 1).
and have the skill set necessary to deal with multi disciplinary
teams, complicated data, and challenging deadlines.
The aim of the PBRER is to present a comprehensive and
critical analysis of the benefit/risk profile of the drug, taking
into account new or emerging information, in the context of
cumulative information. This is to assure RAs that the evolving
risk profile of the drug is adequately monitored. The PBRER
focuses on summarising important relevant safety information
from the reporting period, putting it into context with the
cumulative experience. It is neither a tool to provide relevant
information for the first time nor a “data dump” of extensive
data from individual case reports. In the EU, PBRERs covering up
to 12 months of data are due 70 days after the DLP and reports
covering more than 12 months are due 90 days after the DLP.
It is of utmost importance that the presentation of patient
safety, the drug’s benefit/risk profile, and the MAH’s risk
management assessments to RAs is compliant with
requirements, clear and consistent across the whole suite of PV
documents, and that these documents are produced in a timely
and efficient manner. Involving an experienced PV medical
writer in a product team ensures this, and enables the PV and
medical experts to focus on their core task – patient safety.
Guidelines and Templates
GVP Modules
Visit: www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_
The PBRER is assessed by the RA and feedback is provided to
the MAH in the form of assessment reports. In these reports,
an authority may request more detail on existing issues, or for
new safety topics to be addressed in the next PBRER. PV medical
writers have to guide teams through the relevant topics, advise
on the level of detail, and manage the report timeline. Especially
when writing for drugs on a six month periodicity, good time
and project management skills are essential, considering that
the assessment report for the last PBRER can be expected when
the team is already writing the next report. The DSUR, PBRER,
and RMP are designed to be modular documents, meaning that
sections should be common to all three documents. Therefore, PV
medical writers also have to ensure that the content of the PBRER
is consistent with the information provided in the parallel DSUR
and the potential RMP update.
Management of global PBRER periodicities and frequencies poses
an enormous challenge to MAHs worldwide. DLPs and periodicities
cannot be harmonised globally, eg China and Brazil accept
the PBRER, but have their own DLPs, the Eurasian regions have
different periodicities to the EU, and the US and Canada require
annual reports. The PBRER can be a very large document, and
requires input from many different stakeholders. An experienced
and skilled PV medical writer can work with a dedicated medical
writing group to establish a global report strategy for each drug
so that as few PBRERs are written as absolutely necessary, while
complying with global regulatory requirements.
Although the PBRER, DSUR and RMP are ICH formats and are
widely accepted for submission to most health authorities, local
formats like the PADER and the Investigational New Drug Annual
Report in the US, or the ASR in Canada are often still submitted in
lieu of these reports. Particularly when the PBRER EU periodicity
is over one year, some MAHs prefer to write PADERs as annual
reports and then submit the PBRER, eg every three years.
Conclusion
Since the introduction of GVP, PV has become more complex
and further regulated. This has led to an increasing demand for
medical writers who are familiar with PV documents
listing/document_listing_000345.jsp
DSUR – ICH E2F
Visit: www.ich.org/products/guidelines/efficacy/efficacy-single/article/
development-safety-update-report.html
PBRER – ICH E2C (R2)
Visit: www.ich.org/products/guidelines/efficacy/efficacy-single/article/
periodic-benefit-risk-evaluation-report.html
RMP
Visit: www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_
listing/document_listing_000360.jsp
About the authors
Sven Schirp started his medical writing
career in 1997. He has vast experience
of clinical documentation and medical
writing services, from biomedical
publications and clinical trial reports, to
global marketing applications and PV
documents. Sven is currently Head of
Global PV Writing at Boehringer Ingelheim and manages
the company’s global reporting strategy. He is a thought
leader in PV, and an active member and workshop leader
for the European Medical Writers Association (EMWA).
Email: [email protected]
Lisa Chamberlain James is a Senior
Partner and Chief Executive Officer of
Trilogy Writing & Consulting. Aside from
management activities, she also leads client
projects, with extensive experience in a
variety of documents and a special interest
in drug safety and patient information.
After receiving her PhD in Pathology, Lisa began her medical
writing career in Cambridge in 2000. Since then, she
has been heavily involved in the EMWA on the Education
Committee and as a workshop leader, is chair of the EMWA
PV Special Interest Group, and is a Fellow of The Royal
Society of Medicine.
Email: [email protected]
53
Medical Writing: The Backbone of Clinical Development
Tips and Tricks for Medical Writers:
How to Produce High-Quality
Regulatory Documents
This article will provide useful advice for authors of all types of medical and
scientific regulatory documentation. It can be used as a training tool for new staff
and a repository of helpful reminders for more skilled writers. It is a collection of
rules and suggestions built up over nearly two decades of medical writing experience
and of training and mentoring new medical writers.
Authors are often frustrated that reviewers of their documents
do not focus on the key messages and clinical interpretation
of the data, but instead make numerous corrections of minor
issues such as formatting, abbreviations and punctuation.
What the authors do not realise is that the reviewers cannot
see the wood for the trees. It is a bit like the fact that my brain
could not concentrate on writing this article until I had tidied
my desk and emptied my email inbox! If our documents are
messy, reviewers do not have time to look at what matters
because they are too busy correcting the minor irritations.
I guarantee that if you follow the advice provided in this article
the quality of your documents will significantly improve and
your reviewers will be free to concentrate on the content of
your message instead of its packaging.
Document Structure and Formatting
A well-structured and well-formatted document should be
pleasing to the eye and should help the reader navigate
through its numerous chapters. In regulatory writing, we do
not have much choice about structure as the chapter numbers
are often predefined. Nevertheless, we have the possibility
of inserting additional subheadings which can be invaluable
for organising complex information. We can also use bulleted
lists, bold, italics, paragraphs, tables and diagrams to break up
the text and improve readability. In my opinion, no document
should contain a full page of text with none of the above.
The simplest way to get your formatting right in Word is
to attach a template with pre-set styles. Many companies
also have customised tool bars to facilitate the use of styles
and standardise certain repetitive tasks such as inserting
references and tables. Never copy and paste formatting from
another document unless it has identical Word styles. If in
doubt, always use ‘paste special’ or the ‘keep text only’ paste
option to avoid copying formatting.
Page headers and footers are important as they define the
identity of the document, eg date, version number, study
number etc. Do not forget to update these for each draft and
54
l
February 2017
By Helen Baldwin
at Scinopsis
Medical Writing Tips
• Chapter numbers should never be typed manually. Create automatic
chapter numbers using Word styles (Heading 1, Heading 2 etc.) and
insert an automatic table of contents (References tab)
• Check consistency of the use of capitals in chapter headings.
• Use the ‘navigation pane’ (View tab) to view the document chapter
headings. If any additional text appears, you probably need to correct
the styles
• Always insert table and figure titles using ‘insert caption’ (References
tab). This allows you to produce a table of contents and to insert crossreferences (References tab)
• Use ‘cross-reference’ (References tab) for all references to chapters,
tables, and figures. Check that the hyperlinks function correctly
• ‘Refresh’ your document regularly (CTRL+A then F9) to ensure that all
automatic numbers are correct. Avoid use of page breaks or adding
carriage returns to position text on a new page. It is better to use ‘keep
with next’ (Layout tab, paragraphs, line and page breaks) to ensure
that chapter headings stay with text, and that tables stay with their
captions and footers
• Make sure that bulleted lists are consistent throughout with respect
to symbols, indentation, and choice of punctuation at the end of each
line (. , ; or blank)
• Use non-breaking hyphens (CTRL+Alt+Hyphen) to avoid
hyphenated words splitting across lines and non-breaking spaces
(CTRL+Alt+Space) between numbers and their units to avoid ending
a line with a number
in all sections of the document. For more advice, please refer
to the medical writing tips above. Table 1 consists of Word
shortcuts that are useful for medical writers.
Harmonisation
It is essential to decide what terms to use, and then to stick
to them throughout the whole document. Readers do not
like to have to keep switching between words that look
different but are really saying the same thing. So define your
terms from the beginning and then be consistent. It is also
important to reach an agreement with the statistician to
ensure harmonisation between the statistical tables and your
text. Below are some of the most important concepts and
terms that should be consistent.
British versus American Spelling
Many scientific words are spelt differently on the two sides
of the Atlantic (see Table 2). It is important to choose one
‘language’ or the other. The choice may depend on the
instructions for authors, company style guide, or whether
you are writing for Europe or the US.
Medical writing tip: Set your spellchecker to the correct
language and be careful when you copy and paste text from
other sources in case the language changes.
‘Subjects’ versus ‘Patients’
Some companies describe participants as ‘subjects’ in Phase
1 studies (because they are usually healthy as opposed to
having the disease to be treated) and as ‘patients’ in Phase 2-4
studies. Other companies use a single term for all study types,
so check this before you start.
Medical writing tip: You can use CTRL+F to search for both
words to check you have used one term consistently. However,
do not automatically replace one with the other as this can
lead to mistakes, eg ‘subjective’ becomes ‘patientive’.
Investigational Product Names
Harmonise the product names and avoid switching between
generic names, trade names and internal product numbers.
Treatment Group Names
Think about these carefully as you will have to repeat them
many times throughout your document. Decide whether the
dose and route of administration need to appear in the group
name or not. Generally, these are only needed if they are
A well-structured and
well-formatted document should
be pleasing to the eye and help
the reader navigate through its
numerous chapters. In regulatory
writing, we do not have much
choice about structure as the
chapter numbers are often
predefined
different between groups. Say, for example, you are writing a
clinical study report about a study with three treatment groups:
• Drug A 5mg orally once daily for seven days
• Drug B 10mg orally once daily for seven days
• Placebo orally once daily for seven days
‘Orally once daily for seven days’ is identical for each group so it
could be deleted from the group names. However, the dose is
needed as it varies.
Visit Names
A visit could be called ‘Day 30’, ‘Week 4’, ‘Month 1’, ‘End of
Action
Shortcut
Capitals, no capitals or first letter capitals
SHIFT+F3
Repeat last action
F4
Update fields (refresh)
F9
Cut
CTRL+X
Copy
CTRL+C
Paste
CTRL+V
Paste special
CTRL+ALT+V
Copy format (paintbrush)
CTRL+SHIFT+C
Paste format (paintbrush)
CTRL+SHIFT+V
Select all
CTRL+A
Bold
CTRL+B
Italic
CTRL+I
Underline
CTRL+U
Centre text
CTRL+E
Left align text
CTRL+L
Right align text
CTRL+R
Undo
CTRL+Z
Re-do
CTRL+Y
Non-breaking space
CTRL+SHIFT+Space
Non-breaking hyphen
CTRL+SHIFT+Hyphen
Table 1: Useful Word shortcuts
55
British
American
Words spelled with ‘ae’
aetiology, anaemia, anaesthesia, glycaemic, gynaecology,
haematology, haemophilia, ischaemia, orthopaedic, paediatric
Words spelled with ‘e’
etiology, anemia, anesthesia, glycemic, gynecology, hematology,
hemophilia, ischemia, orthopedic, pediatric
Words spelled with ‘oe’
diarrhoea, foetus, gonorrhoea, oestrogen
Words spelled with ‘e’
diarrhea, fetus, gonorrhea, estrogen
Words spelled with ‘our’
behaviour, colour, favourable, rigour, tumour
Words spelled with ‘or’
behavior, color, favorable, rigor, tumor
Words ending in ‘re’
centre, goitre, litre, millimetre
Words ending in ‘er’
center, goiter, liter, millimeter
Words ending in ‘ise’ or ‘yse’
analyse, dialyse, emphasise, paralyse, randomise, realise,
specialise, standardise
Words ending in ‘ize’ or ‘yze’
analyze, dialyze, emphasize, paralyze, randomize, realize,
specialize, standardize
Other words
aluminium, grey, sulphur
Other words
aluminum, gray, sulfur
Table 2: British versus American spelling
Wash-Out Period’ etc. Choose one name for each visit
and stick to it. This is particularly important for clinical
study protocols and avoids confusion for the investigators
later. Whenever possible, choose meaningful names,
eg ‘Month 6’ provides more information than ‘Visit 6’.
Study Names
In certain documents, for example summaries of the
common technical document, you may have to refer
to several studies many times. Simply using the study
numbers may not be helpful as people outside your
company will not know what they refer to. The full study
titles are probably too long to use. So define short, relevant
names in agreement with the project team and use
them consistently.
Medical Writing Style:
The Importance of Being Clear and Concise
I am a pharmacologist, not a linguist, and I would
not pretend to know everything about grammar or
writing style. However, I do have many years of experience
of reviewing text written by junior medical writers,
and there are a few key points that I try to teach new
writers as I believe they significantly enhance
readability. I would like to share some of this
advice here:
Use Short, Single Topic Sentences
Let your reader breathe. If you need to take a breath while
reading your sentence, it should probably be split into two
or three sentences.
Avoid Repetition
It is often advisable to change the word order in a sentence
in order to avoid repetition.
• Example: Group A had a mean systolic blood pressure of
13.3mm Hg on Day 1 and Group B had a mean systolic blood
pressure of 15.6mm Hg on Day 1
• Improved version: The mean systolic blood pressure on Day 1 was
13.3mm Hg in Group A and 15.6mm Hg in Group B
I only advise using ‘respectively’ for studies with three or more
groups. It requires a little more mental gymnastics to understand.
Put the Most Important Information
at the Beginning of the Sentence
• Example: During the 13-week treatment period, 3.6% of subjects
in the Drug A group and 2.3% of subjects in the placebo group
reported headaches
The sentence is about headaches, so it needs to be mentioned
first. That way, anyone who is not interested in headaches
does not have to read it.
Long
Short
A greater number of
More
A higher proportion of
More
The majority of
Most
Most of the
Most
Higher compared with
Higher than
With the exception of
Except
In order to
To
Table 3: Long phrases and how to shorten them
56
Hopefully, if you follow this advice, you will find that reviewers
focus on the content and clinical interpretation instead of what may
sometimes seem like petty details such as punctuation at the end of
your bulleted lists
• Improved version: Headaches were reported by 3.6% of subjects
in the Drug A group and 2.3% of subjects in the placebo group
during the 13-week treatment period
Use ‘Parallel’ Sentences
Keep the order of sentences the same wherever possible. Once
again, this avoids the reader having to perform mental gymnastics.
• E xample: Osteoporosis was reported for 10% of women and 2%
of men. The data showed that 5% of men versus 15% of women
suffered from headaches
• Improved version: Osteoporosis was reported for 10% of women
and 2% of men. Headaches were reported for 15% of women
and 5% of men
Do Not Try to Sound Clever by Using Fancy Words
In English literature, using different words to say the same thing
is encouraged as it makes the text more interesting. However,
you should not need a thesaurus to read a scientific document.
When writing scientific texts, just use the same wording to say
the same things throughout your document and that way the
reader will be sure to understand the data.
Do Not Waste Words
Many writers seem to believe they appear more intelligent if they
use as many words as possible. However, your job is to make the
reader feel that he/she is intelligent because they understand
your text easily! The best way to do this is to write clear, succinct
text without superfluous words. Table 3 lists a few examples of
common longer phrases, which can easily be shortened.
It drives me crazy when I read a phrase such as: ‘A higher
proportion of patients in Group A had adverse events compared
with those in Group B’. We can simply say: ‘More patients in Group
A had adverse events than in Group B’. Can you imagine how
strange we would sound if we said ‘My sister is older compared
with me and she has a greater number of friends’?
Abbreviations
The generally accepted convention is that abbreviations
should be defined at first use and then used consistently
throughout a document. However, the abstract or synopsis
is usually treated as a standalone document. So, define
abbreviations at first use in the synopsis and then again in the
body of the text. Regulatory documents should contain an
abbreviations list, whereas most manuscripts do not (check
instructions for authors). Make sure this list contains all the
58
abbreviations you have used and, equally importantly,
none you have not used.
You may be tempted not to sort out abbreviations in your
first draft. However, be aware that reviewers are often
irritated by this. So you should insert an explanatory
comment at the start of the document.
Medical writing tip: The quickest and safest method for
frequently used abbreviations is to use them throughout the
first draft of your document. Then, when you are nearly ready to
finalise your draft, use CTRL+F to search for the first appearance
and define it there. Also, use CTRL+F to search for the full term
throughout the document in case you have forgotten to use the
abbreviation somewhere.
Conclusion
I hope this list of ideas for how to improve the quality of your
documents will be helpful for new medical writers, as well as
being a useful reminder for more experienced writers. Hopefully,
if you follow this advice, you will find that reviewers focus on
the content and clinical interpretation instead of what may
sometimes seem like petty details such as punctuation at the
end of your bulleted lists. Medical writing can sometimes be
frustrating, but it can also be extremely rewarding, especially
when you get to the end of a long, difficult project and your boss
or your client says: “Well done, you’ve done a really great job”!
Acknowledgements
I would like to thank Kathryn Hall, Magali Le Goff, Antonia
Pickup and Adrian Tilly at Scinopsis for their help with
reviewing and editing this article.
About the author
Helen Baldwin is the founder and
Managing Director of Scinopsis, a
company providing medical writing
services to the pharmaceutical, medical
device and biotechnology industries. With
a PhD in Pharmacology, she previously
worked in preclinical research and clinical
project management. Helen has been involved in medical
writing since 1999 and is a past president of the European
Medical Writers Association.
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Improving Statistical Reporting
in Medical ResearchJournals
An excellent way to improve your professional reputation is to learn how
to interpret and report statistics. Statistical reporting guidelines are now
available, and the learning curve for applying them is not steep. You don't need
to know how to answer statistical questions, only how to ask the right question
at the right time. The reporting problems described here are among the most
common and illustrate how easily some of them can be recognised.
“The medical literature is plagued by poor
reporting of research studies hindering its
utilisation in clinical practice and further research.
This is unethical, wasteful of scarce resources and
even potentially harmful”
Douglas Altman & Alison Hirsch, 2012 (1)
The Problem of Poor Statistical Reporting
Since the first P value was reported in the mid 1930s, hundreds
of studies have found that large numbers of articles in the
clinical literature contain statistical or methodological errors
(2-9). Furthermore, most of these errors are serious enough that
they threaten the validity of the authors’ conclusions (5,10). The
problem is especially serious because most of these studies are
of the world’s leading peer-reviewed medical journals.
Many of these errors are in basic, not advanced, statistical
methods (10). In fact, authors are far more likely to use only
elementary statistical methods, if they use any at all (1113). Thus, the problem of poor reporting is long-standing,
widespread, potentially serious, concerns mostly basic
statistics, and yet is largely unsuspected by most readers of the
biomedical literature (14). Nevertheless, the first comprehensive
guide to reporting statistics in medicine and the first complete
set of statistical reporting guidelines suitable for a journal’s
instructions for authors were developed recently and not by
statisticians or physicians (14,15).
In this chapter, I describe some of the most common statistical
reporting errors in medical journals. There are many more
where these came from.
By Tom Lang at Tom
Lang Communications
and Training International
Choices in Measures of Centre and Dispersion
Distributions of data are often described with a “measure of
centre,” such as the mean, median, and mode, and with a
“measure of dispersion,” or spread of the data, such as the
standard deviation, range, or interquartile range. From
habit, many researchers report distributions as means and
standard deviations. However, standard deviations, and to
a lesser extent, means, are meaningful only for more-or-less
normally distributed data, and most biological data are not
normally distributed. Thus, other descriptive statistics are
often indicated.
Percentages
In small samples, a few values can be a large percentage of
the total, which can be misleading: “33% of the rats lived, 33%
died, and the last one got away.” For this reason, percentages
should not be used for small samples, say, less than 25, and the
numerator and denominator on which a percentage is based
should always be readily available to the reader.
Problems with Reporting Measures
of Relationships
Tests versus Measures of Association
Association describes relationships between categorical
(usually nominal) variables. Most often, association is
assessed with a test of association and is declared to
be simply present or absent by whether the P value is
statistically significant or not. In contrast, measures of
association indicate the strength of the relationship. For
example, the phi coefficient ranges from +1 (a perfect
positive association) to -1 (a perfect negative association),
where values farther away from zero indicate a stronger
direct or inverse association, respectively.
Problems with Reporting Descriptive Statistics
Errors in Basic Math
Authors make lots of counting and mathematical errors.
In an unpublished study by the Department of Medical
Editing Services at the Cleveland Clinic, 21 of 32 consecutive
manuscripts received for editing had errors in basic math. This
problem of carelessness with numbers has been noted for
almost 60 years (16).
Correlation
Correlation coefficients describe relationships between
continuous variables. These coefficients also range from
+1 (a perfect positive correlation) to -1 (a perfect negative
correlation). Some authors insist that coefficients between 0
and +0.3 (or -0.3) indicate a weak correlation, those between
+0.3 and +0.6 indicate a moderate correlation, and those
between +0.6 and 1 indicate a strong correlation. In fact,
February 2017
l
59
Measure of risk for death by prostate cancer
Value
• Absolute risk with watchful waiting
7%
• Absolute risk with prostate resection
15%
• Absolute risk reduction with resection
8%
Risk ratio for watchful waiting (versus resection)
2.14
Relative risk reduction with resection
53%
Odds with watchful waiting
0.18
Odds with resection
0.08
Odds ratio with watchful waiting
2.25
5-year hazard rate with resection
0.4%
Number of patients needed to treat with prostatectomy to prevent 1 more death
12.5
• Natural frequency, watchful waiting
15 of 100 men
• Natural frequency, resection
7 of 100 men
Table 1: Risk of death from prostate cancer treated with watchful waiting or prostate resection. These nine measures of
risk are common and accurate indications of the probability of death from prostate cancer. They all have their uses, but each
gives a different impression of the risk involved. For example, compare the absolute risk reduction for resection with the relative
risk reduction. The absolute risk, absolute risk reduction, and natural frequencies are probably the easiest for most people to
understand (in this example, 14 of 200 men treated with resection died, and 30 of 200 men with watchful waiting died)
there are no meaningful arbitrary cut points for degrees of
correlation. Coefficients have to be interpreted in light of
the medicine. The concentration of a drug in an IV infusion
should be highly correlated with serum concentration; even a
coefficient of 0.85 may be unacceptably low.
Choice of Measures of Risk
Risk can be reported in several ways, some of which can be
misleading and some of which are more easily understood than
others (see Table 1). The absolute risk should always be reported,
because the other measures of risk can be derived from it.
Problems with Reporting Hypothesis Tests
Hypothesis tests are statistical procedures used to determine
the probability that chance is a plausible explanation for a
relationship indicated by the data, such whether the mean
values of three groups differ or whether two variables are
correlated. If this probability is low (typically <0.05), chance
is discarded as an explanation, and the relationship is
considered to be real.
Violations of Assumptions
All hypothesis tests are based on assumptions about the data
that, if violated, should reduce confidence in the results.
One commonly violated assumption is that data are
“independent”, such as coming from separate patients, when
they are actually paired, in which they come from the same
patient. An unpaired test does not account for changes in the
post-test scores of individual patients, for example, whereas
a paired test does.
Another commonly violated assumption is that data are
linearly related, in which case they can be analysed with linear
regression analysis. However, linearity should be verified,
60
often with an “analysis of residuals,” which is a graph of the
differences between the actual and predicted values of each
data point. Small differences close to zero all along the X-axis
indicate that the data are linear; other patterns do not.
Low Statistical Power
A statistical power calculation computes the number of
subjects who need to be studied to have a given probability
of finding a given difference, if such a difference exists in the
population studied. The “given probability” is the statistical
power coefficient. A coefficient of 80% or 90% is typical.
The difference of interest is usually the “minimum clinically
important difference.” If statistical power is inadequate – that
is, if the sample is too small – a nonsignificant P value does not
necessarily mean that the groups are similar: “absence of proof
is not proof of absence.” In such cases, the study results are not
negative, they are inconclusive.
Misinterpreting P Values
Probably the most common statistical error in the literature
is assuming that a statistically significant P value indicates a
biologically important difference. A P value is a measure of
chance as an explanation for a difference; it has no clinical
meaning. The actual difference – the “effect size” – should be
interpreted in the context of the study, and it may be important
whether the P value is significant or not.
Not Reporting Confidence Intervals
A confidence interval is a measure of precision for an
estimate. The difference between groups, say, is actually an
estimate and thus should be accompanied by a confidence
interval. A 95% confidence interval identifies the range of
values in which we would expect the difference between
groups (the estimate or effect size) to fall in 95 of 100
similar studies.
7
Weaker model,
smaller r2
6
B
5
Stronger model,
higher r2
4
3
2
A
1
0
0
1
2
3
4
5
6
7
8
9
Figure 1: A simple linear regression model: Y=1+0.6X, where 1 is the Y-axis intercept point, 0.6 is the regression
coefficient or beta weight, and X is the value of the predictive variable. Here, for each 1-unit increase in X, Y will increase by
0.6 units, which is the slope of the regression line (the solid line in the figure), calculated as the “rise over the run,” or 5/8 (0.6) in
this case. The wider pair of dotted lines is the confidence band for the slope of the regression line when the model does not fit
the data as well as a model with the narrower confidence band. Thus, the coefficient of correlation, r2, is smaller (closer to zero)
for the wider confidence band and larger (farther away from zero) for the narrower band. The bands flare at the ends because
typically there are fewer data points on the ends of the distribution of values of X. Less data means a weaker estimate and
hence, a wider confidence interval for those values of X. Two other mistakes are A) extending the regression line beyond certain
threshold values. For example, birth weight can never be zero, so the line should not be extended to the Y-axis. B) Assuming that
the regression line will stay linear for values of X beyond the data collected. There are no guarantees that the line will continue to
have the same slope or shape in areas for which data have not been collected
“The drug lowered systolic blood pressure by a mean of
18 mm Hg (95% CI = 2 to 34 mm Hg; P = 0.02)”
In this one study, the drug resulted in a mean 18-mm
Hg drop in blood pressure, and the drop was statistically
significant. The confidence interval, however, is
“heterogeneous”: it contains both clinically important
values at the high end and unimportant values at the low
end. That is, in 95 of 100 similar studies, we might or might
not get a clinically important reduction in blood pressure.
So, rather than claim that the study result is positive on
the basis of a single P value, we have to acknowledge that
it is inconclusive. When the interval is “homogeneous,” or
includes only clinically important or only unimportant
values, we can make a more definitive conclusion.
Confidence intervals, with their associated estimates, keep the
attention focused on the medicine and away from P values
when interpreting results. Many journals now prefer confidence
intervals instead of P values for this reason.
Problems with Reporting Regression Analyses
Regression analyses are a class of statistical tests used to
predict an unknown value of one variable from the known
values of one or more predictor variables. Simple regression
models (either linear or logistic) have a single predictive
variable; multiple regression models have two or more. Linear
regression models (simple or multiple) predict a continuous
value (eg, triglyceride concentration); logistic regression
models predict a binomial value (eg, survival or death).
61
Not Reporting the Model’s Goodness of Fit
In any regression analysis, we need to know how well
the model predicts the variable of interest. One measure
of this “goodness-of-fit” to the data is the coefficient of
determination, r2, for simple regression models, and the
coefficient of multiple determination, R2, for multiple
regression models. These coefficients range from zero to 1,
with higher values indicating better predictive abilities (see
Figure 1). Other measures exist.
allergy and respiratory disease, Pediatr Allergy Respir Dis 21(3):
pp144-155, 2011
6. Al-Benna S et al, Descriptive and inferential statistical methods used in
burns research, Burns 36(3): pp343-346, 2010
7. Barbosa FT and de Souza DA, Frequency of the adequate use of statistical
tests of hypothesis in original articles published in the Rev Bras Anestesiol
between January 2008 and December 2009, Rev Bras Anestesiol 60(5):
pp528-536, 2010
8. Kurichi JE and Sonnad SS, Statistical methods in the surgical literature, J Am
Coll Surg 202: pp476-484, 2006
Not Reporting the Model-Building Process
The model-building process consists of selecting candidate
variables even remotely related to the endpoint, often
those with a P value of 0.1 or 0.2 for their relationship
with the predicted variable. Candidate variables are
then screened for colinearity and interaction. Colinear
variables add the same information to the model, so only
one is used. Interacting variables produce a result greater
than that of their separate results (eg, the combination
of sub-lethal doses of alcohol and barbiturates can cause
death.) This interaction must be accounted for by adding an
“interaction term” to the model.
9. Jaykaran and Jadav P, Quality of reporting statistics in two Indian
pharmacology journals, J Pharmacol Pharmacother 2(2): pp85-89, 2011
10. K
im M, Statistical methods in Arthritis & Rheumatism: Current trends,
Arthritis Rheum 54(12): pp3,741-3,749, 2006
11. R
eed JF 3rd et al, Methodological and statistical techniques: What do
residents really need to know about statistics?, J Med Syst 27(3): pp233238, 2003
12. A
ljoudi AS, Study designs and statistical methods in the J Fam Comm Med:
1994-2010, J Fam Comm Med, 20(1): pp8-11, 2013
13. L ee CM et al, Statistics in the pharmacy literature, Ann Pharmacother, 38
(9): pp1,412-1,418, 2004
14. L ang TA and Secic M, How to Report Statistics in Medicine: Annotated
Guidelines for Authors, Editors, and Reviewers, 2nd edition, American
Candidate variables remaining after screening are then
combined using any of several variable-selection methods, such
as forward, backward, stepwise, and best-subset techniques.
College of Physicians, Philadelphia, 2006
15. L ang TA and Altman DG, Statistical analyses and methods in the published
literature: The SAMPL Guidelines, Moher D et al editors, Guidelines for
Reporting Health Research: A Users’ Manual, Hoboken, NJ: John Wiley &
Not Validating the Final Model
Validating the model means to test how well it predicts, usually
on a different set of data. One of several methods is the splithalf technique, where the model is developed on a portion of
the data and then tested in the remaining data to see how well
it predicts.
Conclusions
Evidence-based medicine is literature-based medicine.
By applying statistical and methodological reporting
guidelines, medical writers and editors can assure
that research designs and activities are appropriately
documented, greatly improving the quality of manuscripts
and the literature and, hence, the evidence on which
medical care is based.
References
1. Altman DG and Hirst A, Are peer reviewers encouraged to use reporting
guidelines? A survey of 116 health research journals, PLoS One 7(4): e35621,
doi: 10,1371/journal,pone,0035621, 2012
2. Mainland D, Chance and the blood count, Can Med Assoc J 30(6): pp656658, 1934
3. Prescott RJ and Civil I, Lies, damn lies and statistics: Errors and omission in
papers submitted to Injury 2010-2012, Injury 44(1): pp6-11, 2013
4. Fernandes-Taylor S et al, Common statistical and research design problems
in manuscripts submitted to high-impact medical journals, BMC Res Notes
4: p304, 2011
5. Lee HJ and Jung SK, The use of statistical methodology in articles in medical
journals and suggestions for the quality improvement of the pediatric
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Sons Ltd, 2014
16. D
avidson HA, Guide to medical writing: A practical manual for physicians,
dentists, nurses, pharmacists, New York: The Ronald Press Company, 1957
About the author
Tom Lang, MA, is Principal of Tom
Lang Communications and Training
International. Formerly Manager of
Medical Editing Services at the Cleveland
Clinic, he also worked at the New England
Evidence-based Practice and Cochrane
Center. He has taught at the University of
Chicago since 1998 and in Asia since 1996. His books, How
to Report Statistics in Medicine, and How to Write, Publish,
and Present in the Health Sciences, are standard references
in medical writing. A participant in the CONSORT, MOOSE,
and QUOROM/PRISMA reporting standards groups, Tom
is also Past President, Council of Science Editors, and
Treasurer, World Association of Medical Editors. He received
the American Medical Writers Association’s highest honor,
the Harold Swanberg Distinguished Service Award for
Outstanding Contributions to Medical Communications
and has teaching awards from the American Medical
Writers Association, the American Statistical Association,
and the University of Chicago. Tom’s Master’s degree in
Communication Management is from the Annenberg School
of Communication at the University of Southern California.
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Clinical Trial Disclosure
and Transparency: Ongoing
Developments on the Need
to Disclose Clinical Data
Public demand and regulatory changes have brought pressure for greatly
improved transparency of information about medicines, clinical trials, and drug
development in general. This article reviews the regulations demanding clinical
trial disclosure as well as its implications on sponsors and marketing authority
holders. It focuses in particular on the disclosure requirements of two leading
regions in this field: the EU and the US.
‘Clinical Trial Disclosure’, with its efforts to increase
transparency of information on clinical trials, is an
established topic for all involved in clinical drug
development. Stakeholders come from across the
pharmaceutical industry, academic institutions and hospitals
performing clinical trials, as well as from groups representing
patients, health professionals and prescribers, and groups
with political-, industry-, economics-, or legislativemotivated interests that are relevant to drug development,
approval, and marketing.
The regions of the world particularly active with regard
to transparency laws on ‘Clinical Trial Disclosure’ are the
European Union (EU), including countries of the European
Economic Area (EEA), and the United States of America (US).
Additional national disclosure obligations also apply in some
40 countries world-wide.
Current Disclosure Obligations and Requirements
EU/EEA and US
Key issues regarding disclosure are defined by Regulation
(EU) No 536/2014, which was issued on 16 April 2014 and
will come into force in 2018 (1). In the interim, the applicable
laws are the Clinical Trials Directive 2001/20/EC and the
Paediatric Regulation (EC) 1901/2006 (Articles 41, 45, 46
in particular) (2). The two main instruments in clinical trial
By Kathy B Thomas
disclosure efforts are the separate legal EU/EEA and US
provisions described in Table 1.
Regulation (EU) 536/2014 harmonises the assessment and
supervision processes for clinical trials throughout the EU via
the EU portal and database. It addresses the publication of
clinical data, including the registration of all interventional
studies and posting of trial result summaries for both
approved and not yet approved medicinal products (1,3).
However, it does not apply to non-interventional studies or
those with medical devices, unless the devices are part of
a trial involving a medicinal product. European regulators
have established a clear distinction between ‘clinical trials’
(‘interventional clinical studies’) and ‘clinical studies’ (1).
Accordingly, the term ‘clinical study’ represents a broader
concept, whereby a ‘clinical trial’ is defined as a specific type
of clinical study.
Implementation of Regulation (EU) 536/2014 is under the
responsibility of the EMA, that also manages the EU portal
and the European Union Drug Regulating Authorities Clinical
Trials (EudraCT) database (www.clinicaltrialsregister.eu).
EudraCT database can only be used for studies performed
in the EU/EEA (ie those studies that have a Eudra number)
or for those associated with regulatory applications in this
region, such as those conducted outside of the EU/EEA in
Regulation (EU) 536/2014 addresses the publication of
clinical data, including the registration of all interventional studies
and posting of trial result summaries for both approved and not yet
approved medicinal products
February 2017
l
63
The EU/EEA (Regulation (EU) 536/2014) (1,3)
The US (FDAAA 801, expanded by Final Rule) (6,7)
Register and disclose all interventional clinical trials with EudraCT number
Register all applicable clinical trials ongoing or
started after September 2007 in the US or as part
of a US regulatory application
Trial registration is performed by the EMA upon receiving the official request for
authorisation of a clinical trial on a medicinal product for human use
Trial registration is performed by the sponsor within 21 days
after enrolment of the first trial participant
Applies to trials ongoing or started:
•A
fter May 2004 in adults
•A
fter May 2006 in children
Applies to trials in:
• Children: Trial category 1, 2, 3[4,8]
• Adults: Trial category 1, 2, 3[4,5]
Applies to trials in:
• Children: Phases 2, 3, 4
• Adults: Phases 2, 3, 4
Disclose summary results for:
Any tested medicinal product, regardless of the regulatory approval status
Disclose summary results for:
Any tested medicinal product, regardless of the regulatory
approval status
Timelines for disclosure of summary results (1,3,18):
• Trials in children within 6 months of last patient last visit (LPLV) (for primary endpoint)[1]
• Trials in adults within 12 months of LPLV (for primary endpoint)[1]
Timelines for disclosure of summary results (6-8):
• For all applicable clinical trials within 12 months of LPLV (for
primary endpoint)[1,2]
Additional documents to disclose:
• Layperson language summary[1]
• Study Protocol (each version and modification)[1]
• Investigational medicinal product dossier (Section S and E)[3,7]
• Investigator’s brochure[3]
• Subject information sheet[3]
• Clinical trial report (redacted)[3]
Additional documents to disclose:
• Full study protocol including all amendments[6]
• Statistical analysis plan including all amendments[6]
Table 1: Clinical Trial Disclosure: A summary of the main requirements in the EU/EEA and the US
In addition to the EU/EEA and the US, other national obligations for disclosure exist in at least 40 countries. National requirements do not necessarily
harmonise in their regulations (details of necessary information, its format, or timelines). Some expect registration of a clinical study protocol only, while
others also require posting of results after a specific time of clinical study completion.
[1] Completion date of an applicable clinical trial is defined as the date that the final subject was examined, or received an intervention for the
purposes of final collection of data for the primary outcome or endpoint – whether or not the study was completed according to the protocol or
was stopped prematurely
[2] D
elayed posting of results with certification is possible. A conditional delayed posting is possible for two additional years (three years in total),
after the completion of the primary outcome or endpoint. The conditions for delay of results posting may include commercial product development
for initial FDA marketing approval or clearance, or approval for a new use (6-8)
[3] Timing of publication of these documents varies, depending on the trial category (3)
[4] For definitions, see Table 2
[5] Currently, data on Phase 1 trials in adults (that are not part of a PIP) are not made public, although this may change. At the time of writing, it was not
clear whether the documents submitted to the EMA for only some or all category 1 trials in healthy adults will be made public
[6] Post study protocol and statistical analysis plan (with all amendments for both documents), at or before the time of trial results information
submission (8)
[7] Structure the IMPD sections (section Q, S, E) as modules that can be easily separated and sent for public posting at required timelines
[8] A paediatric trial is a trial that includes at least one participant less than 18 years of age
so-called ‘third countries’. The EudraCT database contains
details on 29,165 clinical trials as of November 2016.
Another topic of intense interest in the EU is the EMA
Policy 0070, which stipulates a step-wise and proactive
release to the public of ‘clinical reports’, and later of the clinical
trial participant-level data for all studies submitted as part
of a centralised marketing authorisation application in the
EU. Policy 0070 has been in effect since 1 January 2015 and
applies to medicinal products that were approved, but also
to those applications that were rejected or withdrawn (4,5).
In the US, disclosure of clinical study information is legislated
under the FDA Amendments Act of 2007, Section 801 (also
known as FDAAA 801), that expanded in September 2016 by
the final rulemaking (Final Rule), as well as the complementary
64
commitments announced by the National Institutes of Health
(NIH) Policy to share individual trial participant-level data (6-9).
The extended FDAAA 801 law and the NIH Policy comes into
effect on 18 January 2017.
The US law on disclosure is administered by the FDA, managed by
the US National Library of Medicine (a service of the NIH) and uses
the database ClinicalTrials.gov (www.clinicaltrials.gov). The main
purpose of this database is to accommodate applicable clinical
studies performed in the US or as part of an FDA regulatory drug
application. Nevertheless, the database is open to all clinical studies
irrespective of country of origin, sponsor or clinical phase. As of
November 2016, the database contained registration details on
230,427 trials with locations in 193 countries. Most are from non-US
only study sites (46%), 37% are situated only in the US, and 6%
have both non-US and US locations.
Document/item
Content/definition/comment
Citation
Regulation (EU) 536/2014
Regulation (EU) No 536/2014 of the European Parliament and of the Council
of 16 April 2014 on clinical trials on medicinal products for human use and
repealing Directive 2001/20/EC
1
Appendix, on disclosure rules, to the
‘Functional specifications for the EU
portal and EU database to be audited –
EMA/42176/2014’
This document sets out rules and criteria for the application of
Regulation (EU) 536/2014
3
Low-intervention clinical trial[1]
A clinical trial which fulfils all of the following conditions:
(a) the investigational medicinal products (IMPs), excluding placebos, are
authorised
(b) according to the protocol of the clinical trial, (i) the IMPs are used in
accordance with the terms of the marketing authorisation; or (ii) the use of the
IMPs is evidence-based and supported by published scientific evidence on the
safety and efficacy of those IMPs in any of the Member States concerned; and
(c) the additional diagnostic or monitoring procedures do not pose more than
minimal additional risk or burden to the safety of the subjects compared to
normal clinical practice in any Member State concerned
3
Category 1 trial[1]
Pharmaceutical development clinical trials include:
• Phase 1 clinical trials in healthy volunteers or patients; test whether a
treatment is safe for people
• Phase 0 trials – studies in healthy volunteers or patients; explore
pharmacokinetics or pharmacodynamics
• Bioequivalence and bioavailability trials
• Similarity trials for biosimilar products
• Equivalence trials
3
Category 2 trial[1]
Therapeutic exploratory and confirmatory studies include:
• Phase 2 and 3 trials
• Not only trials by the marketing authorisation holder (MAH), but also those
by other researchers looking at safety and efficacy in new indications,
pharmaceutical forms and routes of administration, or patient populations
and not covered by the definition of category 3
3
Category 3 trial[1]
Therapeutic use clinical trials include:
• Phase 4
• Low-intervention clinical trials
3
Table 2: Clinical Trial Disclosure in the EU/EEA: Supporting documents and definitions based on Regulation (EU) 536/2014
[1] Definition that applies for the purposes of the Regulation (EU) 536/2014
Overall, the current regulations in both EU/EEA and the US
require the registration of new clinical trials and posting of
summary results for all completed studies, regardless of the
approval status of the medicinal products. In addition,
the EU/EEA also requires the release of clinical reports
and patient-level data for trials of approved, rejected,
or withdrawn medicinal products. These are described
more fully below and are also summarised in Tables 1, 2
and 3.
Requirements in Other Countries
Publication of clinical trial information is also mandatory
in over 40 other countries worldwide. Unfortunately, there
is no freely available list or electronic database with the
national requirements for clinical trial disclosure. Painstaking
research on national websites is necessary to identify what
is needed. While some only expect registration of a clinical
study protocol, others also demand disclosure of results
by a specified time after study completion. The national
requirements differ in their content, format, or timelines
and thereby present a challenge for sponsors of
multinational trials.
In the current maze of regulatory demands on this topic,
a summary of clinical disclosure requirements in other
countries or world regions would be a very welcome and
useful tool. The WHO might be in a position to take the
stewardship of such a centralised information repository,
which would nicely complement the available clinical trial
search possibilities that are already available on the WHO
website (10).
Requirements by Other Advocates of
Transparency and Disclosure
Declaration of Helsinki 2013
The legally binding regulations for clinical data disclosure in
the EU and the US are in agreement with the latest version
of the Declaration of Helsinki 2013. The Declaration
stipulates the ethical obligation and duty of researchers,
authors, trial sponsors, journal editors and publishers
to register their clinical trials before the start of patient
recruitment, and to follow up with publication and public
dissemination of results (11). Since most study protocols
contain the statement that the “study will be performed in
65
Image: © ssguy – shutterstock.com
agreement with the Declaration of Helsinki”, trial registration
and disclosure are also an ethical requirement. In some
countries, ethics committees and institutional review
boards demand proof of registration of the clinical trial
in a public database.
ICMJE
In 2004, the International Committee of Medical Journal
Editors (ICMJE) stipulated that registration of studies in a
publicly accessible database is a condition for publication
of trial results. Since then, many peer-review journals
have adopted this principle (12,13). In February 2016, the
ICMJE proposed even bolder orders: that data generated in
interventional clinical studies be responsibly shared with
external investigators (14). The suggested data sharing
would require authors to make de-identified individual
patient data (IPD) underlying the results presented in
the article – including tables, figures, appendices or
supplementary material – available no later than six months
after publication. The scientific community’s response to this
proposal has been mixed; the ICMJE have published more
than 300 comments that they have received on their website
and plan to adopt data sharing after considering
this feedback (15).
Pharmaceutical Trade Associations
Trade associations Pharmaceutical Research and
Manufacturers of America (PhRMA) and European Federation
of Pharmaceutical Industries and Associations (EFPIA)
prepared a common document titled ‘Joint principles for
responsible clinical trial data sharing’ that was implemented
on 1 January 2014. This document emphasises the
commitment of the pharma member companies of PhRMA
and EFPIA to disclosing clinical trial data (16).
Registration of New Clinical Trials
EU and US
Laws on the registration of clinical studies aim to ensure
that information about those performed with human
In 2004, the International Committee of Medical Journal
Editors (ICMJE) stipulated that registration of studies in a publicly
accessible database is a condition for publication of trial results. Since
then, many peer-review journals have adopted this principle
66
For an interventional clinical trial in adults completed before
21 July 2014, disclosure of results can be made using the synopsis
of an ICH E3-compliant clinical study report (CSR) or a pre-specified
dataset of summary results (‘full dataset’), or both. For all trials that
have concluded on or after 21 July 2014, the full dataset must be
posted in the EudraCT database
subjects is available or registered in the public domain.
This allows patients and relatives as well as treating doctors
to inform themselves about the availability and suitability
of a study; it also allows full public scrutiny and prevents
selective dissemination of results that can distort the
medical evidence. It enables doctors, prescription
guideline writers, payers and formulary decision-makers
to recommend and provide the right drugs for the
right patients.
Legally binding trial registration of a trial requires
submission of a dataset comprising substantial detail
on each study, including the indication, all primary and
secondary outcomes, the estimated number of participants
and time of outcomes completion. Updates of information
are required. Registration of clinical trials in a public
database is managed in various ways (see Table 1. In the EU,
after sending an application for authorisation to perform a
study to the EMA, selected information fields about the trial
are released to the public sector of the EudraCT database
automatically by EMA representatives.
In the US, the responsibility to register a trial resides with
the sponsor; a proof of compliance must be supplied to
the FDA by completing Form FDA 3674 (Certification of
Compliance). Regular updates of the registration database
entries are obligatory at least annually, even if no changes
are necessary; status changes in participant recruitment
must be updated within 30 days.
Posting of Summary Results
EU/EEA
Under EU law, posting of results in the EudraCT public database
has been mandatory for all clinical trials since 21 July 2014.
Particularly stringent rules regarding the timing of the submission
and the format of results apply to trials involving children (in
which at least one participant is under 18 years of age). Even the
unintended inclusion of a trial participant under 18 years of age
turns the study into one covered by paediatric rules.
For an interventional clinical trial in adults completed before
21 July 2014, disclosure of results can be made using the
synopsis of an ICH E3-compliant clinical study report (CSR)
or a pre-specified dataset of summary results (‘full dataset’),
or both. For all trials that have concluded on or after 21
July 2014, the full dataset must be posted in the EudraCT
database. The usual timeline for releasing results of trials
in adults is within 12 months from the primary endpoint
completion date, but all paediatric trials must have their
outcomes posted within six months from the primary
endpoint completion date. The timelines and modalities for
publishing results in the EudraCT database are explained in a
document provided by the EMA (see Table 1) (17).
Other regulatory documents associated with a trial (clinical
summary, layperson’s summary, clinical protocol and the
CSR) are also required to be posted publicly. Data must
be available in an easily searchable format, with related
data and documents connected by the EU trial number.
Hyperlinks should be used to link together the summary, the
layperson’s summary, the protocol and the CSR of one trial,
as well as referring to data from others who used the same
investigational medicinal product (18). The timelines for
posting the various documents depend on the category of
trials (see Table 2) (3).
US
According to the FDAAA 801 expanded by the Final Rule, as
of 18 January 2017, the release of results will be mandatory
within 12 months after final data collection of the prespecified primary outcome measure (primary endpoint
completion date) for all applicable trials, irrespective of the
approval status for the medicinal product. Other regulatory
documents associated with a clinical trial – such as study
protocol, statistical analysis plan and all their amendments –
are also required for public posting, at the time of the results
information reporting at the latest (see Table 1) (7,8).
Disclosure of Clinical Data and
Trial Participants-Level Data
EMA Policy 0070
In the EU, another important pioneering transparency
effort of clinical data has been accomplished by EMA
Policy 0070. This policy deals with the proactive release
of clinical data and applies to documents on medicinal
products that were submitted as part of the procedure for
67
Document/item
Content/definition/comment
Citation
EMA policy on
publication of
clinical data for
medicinal products
for human use
Developed by the EMA in accordance with Article 80 of Regulation (EC) No 726/2004
5
External
guidance on the
implementation
of the EMA policy
on the publication
of clinical data for
medicinal products
for human use
Topics covered:
• External guidance on the procedural aspects related to the submission of clinical reports for the
purpose of publication in accordance with EMA Policy 0070
• External guidance on the anonymisation of clinical reports for the purpose of publication in
accordance with the policy
• External guidance on the identification and redaction of CCI in clinical reports submitted to the
EMA for the purpose of publication in accordance with the policy
• Annexes: redaction, anonymisation, templates for documents (letters) submitted, redaction
proposal version process flowchart, workflow for the submission of clinical reports for publication,
sample of justification table for CCI redactions, redaction consultation process flowchart, in and
out of scope of Phase 1 of Policy 0070
4
Clinical data
• Clinical reports and IPD
4
Clinical reports
• Clinical overviews (submitted in module 2.5), clinical summaries (submitted in module 2.7) and
the CSRs (submitted in module 5)
• The following appendices to the CSRs: 16.1.1 (protocol and protocol amendments), 16.1.2 (sample
case report form), and 16.1.9 (documentation of statistical methods)
4
Individual patient
data
• Individual data separately recorded for each participant in a clinical study
4
Protected personal
data
• ‘Personal data’ shall mean any information relating to an identified or identifiable natural person
(‘data subject’); an identifiable person is one who can be identified, directly or indirectly, in
particular by reference to an identification number or to one or more factors specific to his
physical, physiological, mental, economic, cultural or social identity
4
Commercially
confidential
information
• Any information contained in the clinical reports submitted to the EMA by the applicant/MAH
that is not in the public domain or publicly available and where disclosure may undermine the
legitimate economic interest of the applicant/MAH
4
Terms of Use
• Governs the access and use of clinical data that are made available to users
5
Table 3: Clinical Trial Disclosure EU/EEA: Supporting documents and definitions based on EMA Policy 0070
the EU centralised marketing authorisation application
− regardless of whether the application was approved,
rejected, or withdrawn (4,5). As such, Policy 0070 tries to
establish an opportunity for secondary research on studies
and the claims made for tested medicinal products.
Policy 0070 separates clinical data into clinical reports
and IPD. The term ‘clinical reports’ includes several key
regulatory documents that are submitted as part of the
centralised marketing authorisation procedure. IPD means
individual data, separately recorded for each participant
in a clinical trial (ie trial participant-level data), as
listed in Table 3.
The EMA is implementing Policy 0070 in two phases:
• Phase 1: concerns the proactive publication of anonymised
clinical reports submitted to the EMA starting from
1 January 2015
•P
hase 2: focuses on the publication of de-identified IPD.
The EMA will execute this phase at a later date that has not
yet been specified
The proactive nature of the disclosure implies that sponsors
will be required to submit two sets of regulatory documents
68
when preparing their centralised marketing authorisation
application in the EU:
• Full information set: for regulatory reviewers involved in
the scientific evaluation process that will contain all of the
information
• Redacted/de-identified information set: for documents
intended for public release after the decision on the
application has been made. The latter should be a copy
of the clinical reports submitted in the context of the
scientific evaluation procedure, but stripped of elements so
that the trial participants can no longer be identified and
commercially confidential information (CCI) not interpreted
Items that qualify for anonymisation, redaction or deidentification are described by the EMA. All items that are
redacted, anonymised or de-identified by the sponsor have
to be justified using the suggested templates and relevant
consultation methods, and agreed upon by the Agency (4,5).
The EMA has defined a process for public release of clinical
reports such that these are available on-screen for any user
with a simple registration process, and for downloading by
recognised users. Both situations are governed by a dedicated
‘Terms of Use’ agreement, which clarifies that the user of
To ensure consistency across all documents
associated with a particular study, sponsors must establish
an overall company policy that summarises their intentions
in the current data disclosure landscape, and adjust their
internal workflow and standard operating procedures
accordingly
the data shall not, in any case, attempt to re-identify trial
participants or other individuals (4,5).
In October 2016, the EMA announced that a new clinical data
database for Policy 0070 had gone ‘live’ (19). The initial release
of information on just two drugs comprises 260,000 pages of
information in over 100 clinical reports. Data for other drugs
will be added progressively. Once the backlog has been dealt
with, the Agency aims to publish clinical reports 60 days after
a decision on an application has been taken, or within 150
days of receiving the withdrawal letter. According to current
forecasts, they expect to offer access to approximately 4,500
reports per year (see Table 3).
EMA Policy 0070 was processed in parallel to Regulation
(EU) 536/2014, and represents the Agency’s commitment
to continuously extend their approach to transparency.
Nevertheless, it is important to recognise that the Policy
has a wider implication than the disclosure requirements
of Regulation (EU) 536/2014. Policy 0070 also applies to the
publication of clinical trials that are conducted outside the
EU but are submitted to the EMA for marketing authorisation
in the EU.
NIH Initiatives for Sharing Trial Participants-Level Data
At the same time as the American release of the FDAAA
801 Final Rule, the NIH has issued a complementary policy
that applies to all NIH-funded trials – including those
that are not subject to the FDAAA 801 and the expansion
by the Final Rule. According to this policy, in addition to
publicly posting the summary of clinical trials, sharing of
trial participants-level data is also planned. The NIH has
evaluated various models for making this feasible and
useful to researchers (20).
Company and Consortium Initiatives
for Clinical Data Sharing
In parallel to the EMA’s Policy 0070, several international
pharma companies and consortiums have organised
voluntary sharing of de-identified clinical trial participantlevel data in a controlled way (21). The conditions under
which sponsor participants agree to share this data include
a research proposal, a statistical analysis plan,
and a commitment to publish the findings of the secondary
research. The requestors’ proposals are reviewed by an
independent panel that decides whether to grant permission
to release those results (21). Through these efforts, any
individual or organisation can request access to de-identified
trial participant-level data and other supporting documents
from studies. Members of the PhRMA and EFPIA have also
committed to sharing this data according to their company’s
own policy on clinical trial disclosure (16).
Implications of Disclosure
To ensure consistency across all documents associated
with a particular study, sponsors must establish an overall
company policy that summarises their intentions in the
current data disclosure landscape, and adjust their internal
workflow and standard operating procedures accordingly.
Further requirements for regulatory documents and new
tasks for existing ones will increase demands on document
preparation, processing, supervision and quality control.
All of these tasks must be considered when planning
drug development projects regarding timelines, costs,
and staff (22,23).
At the operative level, specific requirements apply to the
release of information. Although these often differ only
slightly from the usual reporting practices of a trial, they
should be planned by the study and data managers. Thus,
for example, results disclosure in the EudraCT database
needs a presentation of the randomised trial participants
by country and by pre-specified age categories.
For the safety section, the number of subjects impacted by
non-serious and serious adverse events must be presented
separately. For the actual non-serious adverse events, a
threshold can be applied (up to 5% of participants affected
in any treatment arm), whereas for serious adverse events
all must be shown. For each serious adverse event, the
following information is required: the number of participants
affected; the number of occurrences; relatedness to
treatment; and all fatalities and fatalities regarding
treatment. Some sponsors use a customised file for
uploading the information on adverse events (eg XML).
69
To cope with the requirements of clinical trial disclosure, a
number of excellent tools have been developed, some of
which are freely available through the internet. These help
in preparing documents that are transparency-compliant
and disclosure-ready and include:
6. Visit: www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.
• A study protocol template for Phase 2 and 3 trials (24)
• An annotated and commented user manual intended to
improve the reporting of interventional trials in CSRs (25)
• Recommendations on preparing layperson
summaries (3,26)
9. Visit: https://s3.amazonaws.com/public-inspection.federalregister.
Publications of trial results in journals should be fully
consistent with respective protocols, study reports, and
entries on company websites, in public registries or
databases. In the global world of the internet, discrepancies
can easily be identified between published papers and
information available in the public arena (27).
13. D
e Angelis CD et al, Is this clinical trial fully registered? A statement from
pdf#page=82
7. Visit: www.gpo.gov/fdsys/pkg/FR-2016-09-21/pdf/2016-22129.pdf
8. Zarin DA et al, Trial reporting in ClinicalTrials.gov – The Final Rule,
N Engl J Med 375(20): PP1,998-2,004, 2016. doi.org/10.1056/
NEJMsr1611785"10.10556/NEJMsr1611785
gov/2016-22379.pdf
10. Visit: www.who.int/ictrp/en/index.html
11. Visit: www.wma.net/en/30publications/10policies/b3
12. C
halmers I et al, All trials must be registered and the results published,
BMJ 346: f105, 2013. doi: 10.1136/bmj.f105.:f105
the ICMJE, N Engl J Med 352: pp2,436-2,438, 2005
14. Taichman DB et al, Sharing clinical trial data: A proposal from the ICMJE,
JAMA 315: pp467-468, 2016
15. D
razen JM et al, The importance – and the complexities – of data sharing,
N Engl J Med 375: pp1,182-1,183, 2016
16. Visit: http://transparency.efpia.eu/uploads/Modules/Documents/data-
Indeed, for some time now, many medical journals have
required the clinical trial registration number from a public
database – or the full version of the final study protocol – to
verify details of submitted study manuscripts against the
information from the public domain. This particularly applies
to the declared endpoints of studies. Ideally, all pre-specified
primary and secondary outcomes of a trial would be
included in the publication, or else a clear declaration of ‘why
not’ should be provided. This could be done, for example,
by referring to the study registration entry in a recognised
public database and thus prevent unacceptable incidents
of undisclosed endpoints or ‘outcome switching’ (28).
sharing-prin-final.pdf
17. Visit: https://eudract.ema.europa.eu/docs/guidance/Trial%20results_
Modalities%20and%20timing%20of%20posting.pdf
18. Visit: www.appliedclinicaltrialsonline.com/transparency-eu-prospective
19. Visit: https://clinicaldata.ema.europa.eu
20. H
udson KL et al, Toward a new era of trust and transparency in clinical
trials, JAMA 316: pp1,353-1,354, 2016
21. L o B and DeMets DL, Incentives for clinical trialists to share data,
N Engl J Med 375: pp1,112-1,115, 2016
22. M
anamley N et al, Data sharing and the evolving role of statisticians,
BMC Med Res Methodol 16 Suppl 1: 75, 2016. doi: 10.1186/s12874-0160172-9.:75-0172
23. Visit: www.emwa.org/documents/transparency%20symposium%20
The recent calls for disclosure of study protocols and raw
data from trial participants show how seriously the matter of
transparency is being taken by journal editors, medical and
scientific communities, the pharma industry, private and public
funders, regulators, politicians and patient groups (23,29).
Innovations regarding the clinical data disclosure are intended to
help fulfil scientific discovery and improve health, while elevating
the entire biomedical research enterprise to a new level of
transparency and accountability (20). Responsible and wise use of
the vast amount of available data should maximise the benefits
and minimise the risks for all involved – in particular, the trial
participants – and, in the long term, help patients in need (15,21).
References
1. Visit: www.ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/
reg_2014_536.pdf
2. Visit: www.eortc.be/services/doc/clinical-eu-directive-04-april-01.pdf
and www.ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/
reg_2006_1901_en.pdf
3. Visit: www.ema.europa.eu/docs/en_GB/document_library/Other/2015-10/
WC500195084.pdf
4. Visit: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_
and_procedural_guideline/2016-03/WC500202621.pdf
5. Visit: www.ema.europa.eu/docs/en_GB/document_library/Other/2014-10/
WC500174796.pdf
70
budapest%20final.pdf
24. Visit: www.osp.od.nih.gov/sites/default/files/Protocol_
Template_05Feb2016_508.pdf
25. Visit: www.core-reference.org
26. Visit: www.ec.europa.eu/health/files/clinicaltrials/2016_06_pc_guidelines/
gl_3_consult.pdf
27. Visit: www.opentrials.net
28. Visit: www.compare-trials.org
29. Warren E, Strengthening research through data sharing, N Engl J Med 375:
pp401-403, 2016
About the author
Kathy B Thomas is an independent
consultant and medical writer with more
than 20 years’ experience in the pharma
industry and academia, and extensive
knowledge of clinical trial disclosure law
in the US and EU. She has worked on
preparing registry entries and developing
internal guidelines, as well as processes to assure
compliance. Previously, Kathy served as Head of Medical
Writing at Altana Pharma AG in Konstanz, Germany.
Email: [email protected]
Medical Writing: The Backbone of Clinical Development
Medical Writing for Submission to
Asia-Pacific Regulatory Authorities
The need for quality medical writing services is growing in Asia.
While some Asian countries follow the ICH guidelines, sometimes
with additional local requirements, others have their own specific
regulations. Medical writers are being called upon to help guide
teams in navigating the different regulations during document
preparation. This article reviews the current landscape for key
regulatory documents for submission to major health authorities in
Asia, and describes how seasoned writers with local knowledge can
contribute to successful submission.
The pharmaceutical market in Asia-Pacific is expanding.
Japan is the largest pharmaceutical market in the region,
at $116 billion, and China is rapidly catching up ($99 billion,
and 18.7% compound annual growth rate projected for
2015-2017). The growth of other Asia-Pacific countries is
also projected at 9-13% over the same period. There is
increasing demand for studies to launch new medicinal
products in the Asia-Pacific region, especially in China and
Japan where regulatory changes are speeding up the drug
review and approval process. Consequently, the need for
medical writing support for the regulatory documents
that make up the marketing approval application is
growing in parallel.
While the documentation required by some Asian regulatory
authorities is largely harmonised with ICH, there are also some
local variations or additional requirements. For economic and
practical reasons, most multinational companies do not have a
medical writing function in each country within Asia. Instead,
they may establish medical writing functions in one or two
hub locations in the region. Medical writers in these teams
may therefore need to be familiar with the regulations for
marketing applications across multiple countries in Asia.
The clinical regulatory documents most frequently
prepared by medical writers in Asia are:
• Protocol and informed consent form (ICF)
• Development safety update report (DSUR)
• Clinical study report (CSR)
• Clinical sections of the marketing application dossier
• Periodic safety update report (PSUR)
• Risk management plan (RMP)
There are many considerations and requirements, some
different from ICH, which medical writers must keep in mind
when preparing these types of documents for key regulatory
authorities in the Asia-Pacific region.
By Julia Cooper, Rui Yang, Henny Wati,
Ryoichi Hirayama, Becky Lu, Sylvia
Kang, Christine Siew, Marissa Laureta
and Supamas Chansida at PAREXEL
China Food and Drug Administration
The Chinese pharmaceutical market is dynamic and
increasingly complex. In the past two years, the Center for
Drug Evaluation (CDE) affiliated to China Food and Drug
Administration (CFDA) has released more than one guideline
or draft guideline seeking public opinion almost every month.
Recent changes include the prioritisation of approval of
certain drug classes in order to accelerate approval times.
Priority drugs include new drugs not yet marketed in China
or overseas, products undergoing simultaneous marketing
application in the US or Europe, products showing clinically
significant superiority for certain diseases (HIV, viral hepatitis,
tuberculosis, oncology, rare diseases), and products intended
for paediatric use (1).
Medical writers are increasingly involved in writing protocols
for studies run in China. The protocol, together with the ICF,
generally follows the content outlined in the ICH E6 guideline.
A pre-approval safety update report such as the DSUR
is not mandatory unless requested by the sponsor or
CFDA. However, this may soon change because the draft
Administrative Provisions for Drug Registration (Revision)
includes a requirement for an annual report during clinical
studies, which will periodically summarise data relating
to drug manufacturing and safety and efficacy data for
preclinical and clinical studies, and will evaluate the
actions taken or to be taken (2).
A CSR guideline was issued by the CFDA in 2005 defining
three types of CSR structure (3): for Phase I tolerability
studies, Phase I pharmacokinetic studies and Phase II/
III studies. The elements of the CFDA CSR guideline are
very similar to ICH E3, but it does have some unique
requirements regarding CSR appendices that are not
covered by the ICH guideline, including individual bysite summaries, and a statistical analysis report. Some
February 2017
l
71
Protocol
China
ICH E6 compliant
ICH E6 compliant
Japan
Must also include:
• No. of Japanese subjects to be enrolled
• Definition of adult as 20 years in inclusion criteria
• Summary of investigational product labelling
• Statement of compliance with Japanese GCP
• Planned study period
• Study organisation appendix listing Japanese clinical sites and vendors
Korea
ICH E6 compliant
Taiwan
ICH E6 compliant
Malaysia
ICH E6 compliant
The Philippines
ICH E6 compliant
Thailand
ICH E6 compliant
ICF
China
Japan
Generally complies with ICH E6. No age threshold specified for signature by adolescents or children.
Adolescents/children should sign the ICF as long as they can understand it. A legal guardian must sign in addition
Follows ICH E6 but more detailed information is required, eg:
• General explanation of a clinical trial
• Data on adverse drug reactions (ADRs) from previous studies, package inserts of similar products and investigator brochure
• Explanation of inclusion and exclusion criteria
ICF should be ‘visually-friendly’:
• Table, charts and pictures are often used
• Font and font size are carefully considered
Korea
ICF follows ICH E6. MOH ICF (Form 34), applies to studies that require human-derived material storage or other usage except for clinical
trial purposes (15)
Taiwan
ICF follows ICH E6, and requires customisation for several local requirements – eg specific terms that cannot be changed, local sponsor
identification and injury liability
Malaysia
The Philippines
Thailand
ICF follows ICH E6. Country-specific customisation is required and a standard checklist is provided by the central EC
ICF follows ICH E6, and requires customisation for several local requirements (templates provided)
ICF follows ICH E6, and requires customisation for several local requirements
companies strictly follow the CFDA guideline for CSRs. In
practice, the CFDA also accepts the CSR body in the ICH
E3 format, if the CSR appendices are supplemented by the
additional documents required to comply with the CFDA
guideline. Data in Chinese patients are required to obtain
marketing approval from the CFDA. These data may be
obtained from a stand-alone China study or by including
Chinese sites within a multi-country study. A recent CFDA
draft guideline clarifies that for a multinational clinical trial,
comparisons between Asian versus non-Asian, and Chinese
versus non-Chinese data must be included in the CSR
(4). A skilled medical writer will be able to help the team
determine how best to present these data.
The format of the CFDA marketing application dossier
is changing. The following new guideline was issued in
May 2016, and is already being followed although it is still
in draft stage: Requirement on Registration Dossier under
the New Categorization for Chemical Drug Registration
(Tentative) (5). This regulation requires inclusion of
72
additional documents not previously specified, such as
a data management plan and data management report.
The draft guideline also refers to The Guideline of the
Structure and Content of Summary Documents for Chemical
Drug – Summary of Clinical Studies (6), the content of which
is similar to Module 2.5 of ICH M4, Common Technical
Document (CTD). For Chinese marketing applications for
drugs already marketed outside of China (category 5), the
CTD modules including the comparisons of Chinese to nonChinese data may be submitted instead of the CFDA dossier
format, if supplemented by Module 1(administrative and
summary section) from the CFDA guideline. If the company
does not have a global CTD to use as the starting point, the
clinical summary guidance may be followed but the actual
structure of the documents may need to be determined
depending on the data to be presented (6).
PSURs are required for marketed drugs, and these
follow ICH E2C. At present there is no requirement for
an RMP in China.
DSUR
China
No requirement for DSUR yet. CFDA requires annual reporting safety information
during clinical development stage; no guidance available
Japan
DSUR required for pre-approval products. ICH E2F compliant. A cover letter in Japanese including executive summary and listing of
SAE cases from Japan are needed in the specific format (7)
Korea
DSUR not mandatory, but MFDS accepts DSUR if submitted
Taiwan
DSUR not mandatory, but should be submitted if available
Malaysia
The Philippines
Thailand
DSUR not mandatory, but submission is encouraged
DSUR required for pre-approval products. ICH E2F compliant
Annual safety report is required. There is a local format, however DSUR is accepted
CSR
China
CFDA guideline for CSR format (3). CSR in ICH E3 format is accepted if CFDA-specific appendices are included:
• Individual by-site summary for multicentre clinical trials
• Statistical report
• Approval letters from ECs, also for all protocol amendments
• Study site qualifications
• Principal investigators’ qualifications
• Certification of analysis and pre-production record (including placebo)
• Package insert for comparator and investigational product (if marketed)
• Chromatograms for samples from all subjects (pharmacokinetic and bioequivalence studies)
Japan
ICH E3 compliant. Separate comparison of Japan versus non-Japan data is required (can be a separate report in Module 5.3.7) (8)
Korea
ICH E3 compliant
Taiwan
ICH E3 compliant plus Taiwan data summary
Malaysia
ICH E3 compliant
The Philippines
Submission of CSR not mandatory
Thailand
Submission of CSR not mandatory
The recent CFDA requirement for sponsors to conduct selfinspection activities places an increasing focus on data quality,
and by implication, the quality of the marketing application
dossier. Overall, there is a general trend towards aligning
quality with international standards, as illustrated by a recent
CFDA decision to accept regulatory and technical guidance
from ICH, EMA, FDA and WHO, to facilitate dual registration
of new drugs. An experienced medical writer can assist not
just in the writing of the documents required in the pre- and
post-approval phases, but increasingly in providing guidance
to the responsible teams to align the strategy with both local
and international standards.
CFDA. A medical writer with local knowledge can also help
the team ensure their approach is up to date, as
the regulations continue to evolve.
At present, the marketing application in China may be one
of the last in a multinational company’s global development
plan, in part due to the long investigational new drug (IND)
and new drug application (NDA) approval times.
The prioritisation of applications for specific drug classes,
as well as plans to increase the numbers of CFDA reviewers
will serve to shorten approval times in the long term. For
now, however, medical writers can contribute to global
submissions by anticipating presentation formats, resource
and timelines for the additional data displays required by
Pharmaceuticals and Medical Devices
Agency (PMDA) – Japan
Although the eCTD is expected to be implemented at some
point, the clinical dossier is currently required as a paper
submission, and timelines must be planned accordingly. In
addition, the study report and submission documents may be
prepared in English if a global team will be involved in the review,
then translated into simplified Chinese for CFDA submission.
Writers with excellent verbal and written English skills, in addition
to Chinese, will be able to ensure this process runs smoothly.
Japan has a Good Clinical Practice (GCP) guideline that
follows the ICH GCP requirements, with some Japan-specific
additions. These include emphasis of the role of the head
of the hospital/institution, in addition to those of the
investigators. To conduct a clinical study, an approval letter
from the head of the investigational site based on Ethics
Committee (EC) approval is required.
73
CTD
China
Structure outlined in CFDA guideline (5). ICH M4 CTD plus module 1 of CFDA dosser accepted for drug already marketed ex-China
(category 5 per new categorisation).
The guideline on Summary of Clinical Studies (6) is similar to CTD Module 2.5
Japan
ICH M4 CTD, with additional assessments of Japanese data (9):
• Module 2.5: comparison of Japanese and non-Japanese data
• Module 2.7.2-2.7.4: separate assessment of Japanese subject data
• Module 2.7.4: Listing of SAE and death cases by study, identifying Japanese vs non-Japanese
• Module 2.7.6: more detailed presentation of disposition of subjects, primary and secondary efficacy analysis, safety analysis and
subject narratives in Japanese for pivotal studies (SAEs and deaths)
Korea
ICH M4 CTD modules accepted but additional Korea-specific documents are required, according to MFDS format (13).
Bridging data from Korean patients is usually required; MFDS published a guideline for bridging data report (12)
Taiwan
ICH CTD is followed. A BSE report may be submitted to request waiver of the bridging study requirement (17). If a waiver is not
approved, the study will need to be conducted and the study report submitted to support the marketing application
Malaysia
ACTD and ACTR guidelines are followed
The Philippines
ACTD and ACTR guidelines are followed
Thailand
Either ACTD or ICH M4 CTD is required, depending on the type of application
Protocols are accepted by PMDA in English although a
Japanese language version is needed for the site personnel.
An appendix of the study organisation, including by-site
listing of clinical sites, with address and name of investigator,
and list of study-related vendors, should be submitted
together with the protocol.
The ICF generally complies with ICH E6, but general
background about clinical trials must be included, as well
as more detailed information on the study procedures
and inclusion/exclusion criteria. In addition, use of visual
components is considered to be important, such as tables,
pictures or certain font types.
DSUR submission is mandatory for clinical trials using preapproval (not marketed) study drug (7). Submission of the
global DSUR in English is accepted if accompanied by Japanspecific cover letters including an executive summary in
Japanese and separate assessments of Japanese cases
in a specified format (Form 1, Form 2).
The CSR is accepted in English in ICH E3 format. Separate
assessments of data in Japanese subjects are required (8).
The marketing application dossier follows ICH M4 CTD
format. Module 1 is prepared in Japanese and includes the
local regulatory requirements. Module 2 is also prepared in
Japanese, but Modules 3, 4, and 5, may be submitted
in English. The Japanese CTD requires a separate assessment
of Japan data in the clinical modules (Modules 2.5 and 2.7),
inclusion of a listing of Serious Adverse Events (SAE) and death
cases in Module 2.7.4, and safety narratives in Japanese for
pivotal studies in Module 2.7.6 (9).
A Post-Marketing Safety Periodic Report is required.
It includes the post-marketing safety survey reports, and
the PSUR is appended. A PSUR in Periodic Benefit Risk
Evaluation Report (PBRER) format is accepted in English for
global studies. For local studies, a PMDA-compliant PSUR
format in Japanese should be used (10).
The RMP is required for new drugs and for biosimilars/follow-on
biologics for applications submitted on or after 1 April 2013,
and follows ICH E2E.
In Japan, writing in local language is very important, as
many documents must be submitted in Japanese, or require
a Japanese cover letter. This typically includes a summary
of the document and will specifically highlight the separate
assessment of Japanese subjects. Overseas sponsors need
to be aware of the additional requirements for Japan. Similar
to China, the medical writer can help the team by helping
to plan timelines and resource for the separate analysis of
Japanese data and the additional documents, and by using
their expertise to help determine the best presentation
of the data.
In Japan, writing in local language is very important, as many
documents must be submitted in Japanese, or require a Japanese
cover letter. This typically includes a summary of the document and will
specifically highlight the separate assessment of Japanese subjects
74
PSUR
China
PSUR guidelines are mainly based on ICH E2C. Major differences are:
• Must be submitted in Chinese or with Chinese translation, except for line listings and summary tabulations
• Any differences between China and other countries, such as drug indications, formulations and dosages, and any safety information,
need to be addressed and explained
• Required annually in new drug monitoring period (3-5 years); thereafter every 5 years
Japan
Post-Marketing Safety Periodic Report is required every 6 months for the first 2 years, then annually until re-examination (drug reexamination system: part of the PMS to examine safety and efficacy data collected during a certain period of time) (10). The report
includes post-marketing survey reports: overview and analysis of the survey, ADRs reported, individual case report of ADRs, actions
taken for safety reasons including any changes to the drug labelling, the package insert, and an analysis of safety.
The PSUR is attached to the Post-Marketing Safety Periodic Report. PBRER format is accepted in English for global studies. For local
studies, a PMDA-compliant PSUR format in Japanese should be used. For non-marketed products, a 6-month periodic report of serious
ADRs is to be submitted, including all serious ADRs reported in and outside Japan
Korea
Periodic PMS report is required every 6 months for the first 2 years, then annually until the end of the surveillance period. The report
must summarise the results of use-result surveillance and special surveillance studies, local and foreign safety data, and sales data (14)
Taiwan
PBRER format plus local appendices (package insert, domestic sales information and analysis of domestic ADRs). Required every 6
months for the first 2 years, then annually for next 3 years
Malaysia
The Philippines
Thailand
PBRER format, required every 6 months for the first 2 years, then annually for next 3 years
PBRER format. For drugs under regular registration: every 6 months for the first 3 years, annually for the next 2 years, thereafter every 2
years
Not required unless requested by Thai FDA
Ministry of Food and Drug Safety (MFDS) – Korea
ICH guidelines are generally accepted by MFDS for the protocol,
investigator brochure, CSR, CTD, periodic safety report, etc.
However, there are some local requirements, listed below:
frequent changes in regulations. As of October 2016, a new
regulation on safety of pharmaceuticals has been announced
(16). The impact is under assessment; however, it does
include updates on requirements for clinical trials.
Taiwan Food and Drug Administration (TFDA)
• In addition to the ICF, Ministry of Health (MOH) ICF (Form #34),
is applicable for clinical studies that require storage of humanderived material or its usage apart from the purpose of the
clinical trial (11)
• The DSUR is not mandatory but is accepted if submitted
• The CSR follows ICH E3. In addition, bridging data from
Korean patients is usually required to obtain marketing
approval, obtained from a stand-alone Korea study,
or by including Korean sites within a global study. The
bridging data report must be included in the marketing
authorisation application. MFDS has published a guideline
for the required content and format (12)
• The marketing application dossier is accepted in ICH M4 (CTD)
format, but additional Korea-specific documents are required,
according to MFDS guidelines (13). The local requirements
mostly concern the chemistry, manufacturing and controls
sections in Module 3. Submission in eCTD format is mandatory
• A periodic post-marketing surveillance (PMS) report must
be submitted every six months for the first two years, then
annually until the end of the surveillance period. The report
must summarise the results of use-result surveillance and
special surveillance studies, local and foreign safety data,
and sales data (14)
• The RMP has been implemented since 2015 and must be
submitted as part of the marketing authorisation application
for new or orphan drugs. Local regulation and guidelines
apply to the RMP format (15)
The Korean regulatory environment is continuously evolving
and medical writers need to keep up to date with the
The regulatory infrastructure is well developed in Taiwan.
Although Taiwan follows most of the global standards,
the medical writer needs to understand the specific local
requirements relating to clinical documents.
ICH guidelines are followed for most documents, eg protocol,
investigator brochure, CSR, and other global standards, eg
US FDA guidance, are accepted. There are additional local
requirements for certain documents:
• The ICF generally complies with ICH E6, although certain
specific terms or template text must be used
• The DSUR is not mandatory. However, according to GCP,
the sponsor should submit all safety updates and periodic
reports to the regulatory authorities, and the ICH E2F
format is accepted
• ICH E3 is followed for the CSR, supplemented with a
summary of the data in Taiwanese patients. The Taiwan
data should generally be compared to non-Taiwan
or global population
• The marketing application dossier follows ICH M4 CTD.
If there are sufficient data to demonstrate ethnic
insensitivity, a bridging study evaluation (BSE) report may
be submitted to request waiver of the bridging study
requirement (17). If a waiver is not approved, the bridging
study will need to be conducted, and the bridging study
report submitted to support the marketing application
•A
PSUR in PBRER format is required every six months for
the first two years, then annually for next three years
75
RMP
China
RMP not required at present
Japan
ICH E2E compliant.
RMP is required for new drugs and biosimilars/follow-on biologics for applications submitted on or after 1 April 2013. The RMP should
be submitted together with a cover letter containing a Japanese summary of RMP in a specific format
Korea
RMP required as part of marketing authorisation application for new drug or orphan drug. Local regulation and guidelines apply (15)
Taiwan
Specific RMP guideline. Product-specific templates apply depending on product risk, eg for TNF-alpha product
Malaysia
The Philippines
Thailand
RMP required for new drug/biologics applications, or for significant change to existing registered product
RMP guideline is in development and will be implemented once available
Not mandatory
• There is a TFDA specific guideline for RMPs. In addition,
depending on the risk of the product, use of productspecific templates, eg for tumour necrosis factor (TNF)-alpha
products, may be required
Malaysia MOH
The Malaysia regulatory environment is well structured
and a guideline is available for submission of clinical trials
in Malaysia (18).
In general, Malaysia has adopted the ICH and EMA guidelines.
• The ICF follows ICH E6 but country- specific
customisation is required and a standard checklist is
provided by the central EC
• The DSUR is not mandatory; however, its submission
is encouraged
• The CSR is mandatory and follows ICH E3
• The marketing authorisation application follows the
ASEAN Common Technical Dossier/Requirement (ACTD/
ACTR) guidelines. The structure is similar to ICH M4,
however there are four parts instead of five modules.
A Clinical Overview and Clinical Summary are required
• A PSUR in PBRER format is required every six months for
the first two years, then annually for next three years
• The RMP will normally be required for an application
involving new drug products or new biologics or for any
significant change to an existing registered product, as
specified in the guidelines
Philippines Food and Drug Administration (PFDA)
The regulatory environment in the Philippines is changing in
line with global standards. The PFDA follows global guidelines
such as ICH guidelines, and a Bureau Circular has been
published on the process of evaluating clinical trials (19).
• There are country-specific requirements for the ICF, and local
templates are provided
• A DSUR is required, and should comply with ICH E2F
• Submission of the CSR is not mandatory but it is best practice
to submit it when available
• The marketing authorisation application follows the ACTD/
ACTR guidelines
• A PSUR is required in PBRER format. For drugs under regular
registration, the PBRER is required every six months for the first
three years, annually for next two years, thereafter every
two years
• A RMP guideline is in development and will be implemented
once available
Thailand Food and Drug Administration (Thai FDA)
The regulatory environment is evolving in Thailand. Guidance
for clinical trial applications was announced and implemented
in August 2015, with further guidance implemented in October
2016 (20). A new guidance implementing electronic submission
for pharmaceutical product registrations for New Chemical
Entity, New Biologicals and Human Vaccines came into effect
in January 2016. Nevertheless, ICH guidelines and other
The regulatory environment is evolving in Thailand.
Guidance for clinical trial applications was announced and
implemented in August 2015, with further guidance implemented
in October 2016
76
3. Visit: www.cde.org.cn/zdyz.do?method=largePage&id=2059
4. Visit: www.cde.org.cn/zdyz.do?method=largePage&id=238
ICH guidelines
are widely adopted in
Asia-Pacific, and there is
increasing alignment with
other global standards.
However, each country
generally has its own local
requirements in addition
5. Visit: www.sda.gov.cn/WS01/CL1434/151985.html
6. Visit: www.cde.org.cn/zdyz.do?method=largePage&id=2075
7. Visit: www.pmda.go.jp/files/000156366.pdf
8. Visit: www.pmda.go.jp/files/000156923.pdf
9. Visit: www.pmda.go.jp/files/000153518.pdf
10. Visit: www.pmda.go.jp/files/000143917.pdf
11. Visit: www.law.go.kr/lsOrdinAstSc.do?menuId=9&p1=&subMenu=1&nwY
n=1&section=&tabNo=10&query=%EC%83%9D%EB%AA%85%EC%9C%
A4%EB%A6%AC&x=0&y=0#
12. Visit: www.mfds.go.kr/index.do?mid=1161&searchClass=&searchDivision
=&searchSubDivision=&searchkey=title%3Acontents&searchword=%B0%
A1%B1%B3&x=0&y=0
13. Visit: www.mfds.go.kr/index.do?mid=1013&division=&searchkey=title%3
Acontents&searchword=%C7%E3%B0%A1&x=0&y=0
14. Regulation for Re-review for New Drugs, 2015-79_2015.10.30
15. Visit: www.mfds.go.kr/index.do?mid=1161&searchClass=&searchDivision=
global standards, eg US FDA guidance, are recognised by the
Thailand FDA. Most of the core documents such as protocol and
investigator brochure follow the global standards and structure.
&searchSubDivision=&searchkey=title%3Acontents&searchword=%C0%A
7%C7%D8%BC%BA&x=0&y=0
16. Visit: www.law.go.kr/lsSc.do?menuId=0&p1=&subMenu=
1&nwYn=1&section=&tabNo=&query=%EC%9D%98%EC
• The ICF must comply with ICH E6, however several countryand site-specific requirements apply
• The CSR is not a mandatory document, although an end-ofstudy safety report is required within six months of end of study
• There is a local format for the annual safety report; however
a DSUR in ICH E2F format will also be accepted
• For the marketing authorisation application, a dossier in either
ICH M4 CTD or ACTD format may be required, depending on
the type of application
• The RMP is not mandatory
%95%BD%ED%92%88%20%EB%93%B1%EC%9D%98%20
%EC%95%88%EC%A0%84%EC%97%90%20%EA%B4%80%ED%95%9C%20%EA%B7%9C%EC%B9%99#liBgcolor0
17. Visit: www2.cde.org.tw/FAQ/NDA/sublink/%E8%A1%9B%E7%BD%B2%E8
%97%A5%E5%AD%97%E7%AC%AC0980303366%E8%99%9F.pdf
18. Visit: http://npra.moh.gov.my/images/Guidelines_Central/Guidelines_on_
Clinical_Trial/2016/CTIL_CTX_Guideline_Edn_6.3_clean.pdf
19. FDA Circular No 2012-007, Recognition of Ethical Review Board/
Committee For Purposes of the Conduct of Clinical Trials on Investigational
Medicinal Products in the Philippines and for Other Purposes, 2012
20. Guideline for Submission of Application for Drug Importation into
Conclusion
ICH guidelines are widely adopted in Asia-Pacific, and there is
increasing alignment with other global standards. However,
each country generally has its own local requirements in
addition. Furthermore, the regulatory environment is evolving
in some parts of Asia-Pacific, and it is important to keep up to
date with local requirements to avoid delays in the submission
approval process.
The quality of the data presentation is important, in addition to
regulatory compliance. Separate analysis of local patient data is
required for some countries, and the writer’s skills are needed
to understand how best to present and discuss this data. Bi- or
even trilingual written and verbal communication skills can
also be essential. The value of the medical writer is achieving
increasing recognition in Asia, and experienced writers with the
ability to contribute local regulatory and writing knowledge are
in demand to assure the success of local submissions as well
as the overall global submission strategy.
References
1. Visit: www.sda.gov.cn/WS01/CL0844/145260.html
2. Visit: www.sda.gov.cn/WS01/CL0778/160300.html
Thailand for Clinical Trials, Thailand FDA, 2016
About the authors
The authors are employed in the Medical
Writing Services (MWS) and Clinical
Trials Regulatory Services (CTRS)
departments at PAREXEL. Julia Cooper is
Vice President, Head of Global MWS and
currently based in PAREXEL’s Shanghai,
China office. The MWS team also includes: Rui Yang,
Associate Director Asia-Pacific based in Beijing, China;
Henny Wati, Senior Manager, working out of Singapore;
and Ryoichi Hirayama, a Principal Medical Writer located in
Osaka, Japan.
The CTRS team consists of Sylvia Kang, Senior Manager
in Seoul, South Korea; Christine Siew, Associate Manager
in Petaling Jaya, Malaysia; Marissa Laureta, Associate
Manager in Makati, the Philippines; and Supamas Chansida,
Associate Manager based in Bangkok, Thailand. Becky Lu is
Director of Regulatory Affairs, based in Taipei, Taiwan.
Email: [email protected]
77
Medical Writing: The Backbone of Clinical Development
Managing or Outsourcing
your Medical Writing
As medical writing has advanced as a functional competency, a variety
of business models have been developed (in-house writing, full-service
outsourcing, functional service provider models, use of sole proprietors/
freelancers, etc) to enable pharmaceutical companies to deliver high-quality
document work on time and on budget. The talents and skill sets that make for
great medical writers are not always the same talents and skill sets required
to partner effectively between companies, to measure and ensure quality,
and to drive efficiency across a portfolio of work. This article focuses on best
practices and winning strategies for managing or outsourcing medical writing
deliverables within this complex business environment. Suggestions on how to
kick-off effective working relationships, measure and optimise performance,
and how to innovate through partnership are discussed.
Introduction
The expectations within the pharmaceutical industry for
excellence in regulatory document work have never been
higher. The diversity of regulations and document types globally
continues to expand, while the expectations around document
quality and transparency and the downward pressures on cost
and speed are immense. As a result, the profession of medical
writing has advanced tremendously in the past 20 years.
As the profession has evolved, so too have the employment
opportunities for medical writers. Medical writers are employed
within pharma companies, by large and small CROs, by thirdparty companies that specialise in medical writing services, for
themselves as sole proprietors, and just about everywhere else in
between. As a result, there are a number of different “engagement”
models for how and where document work gets done – providing
great opportunity and flexibility in how documents are developed
but creating potential obstacles in the forms of complexity
and the need to successfully manage business-to-business
relationships. Balancing these opportunities and challenges can
be achieved through the implementation of best practices for
successful partnerships between Sponsors (usually pharma or
biotech companies) and Service Providers (CROs, freelancer/sole
proprietors, medical writing companies, etc).
Types of Service Providers
Due to the diversity of Service Providers, a number of different
partnership arrangements are available to Sponsors, each with
their own set of advantages. Matching the correct medical
writing Service Provider to the right set of document work is
becoming increasingly challenging. But finding a good fit for
the size of the Sponsor and the volume and complexity of the
document work to be done can be very valuable in terms of
78
l
February 2017
By Michael John Mihm
at Astellas Pharma and
Cortney Chertova at
Randstad Life Sciences
delivery, timeliness, cost, and even enhancing the quality of
the work itself. Table 1 displays some of the more common
partnership arrangements and compares important aspects
for each model.
In general, the selection of medical writing models is dependent
on a variety of factors. For programmes with a limited scope or
those that require an individual niche expertise (either document
type or therapeutic area), freelancers can be an excellent choice.
But due to their limited capacity as individuals, freelancers may
not be the right choice for more complex or expansive projects.
Full-service CROs can be very convenient for the delivery of
study-related documents for a particular outsourced trial or
programme. Functional service providers (FSPs) represent an
area of innovation in medical writing partnerships, creating
opportunities for efficiency and optimisation across larger
document plans and programmes. However, an FSP model
requires substantial initial training investment from both the
Sponsor and the FSP itself. This initial training investment is
aimed at producing writers who are not only well-versed in the
Sponsor’s document style but also have a deep understanding
of the Sponsor’s drug programmes.
Starting and Maintaining a Relationship
A medical writing partnership requires an initial investment to
define not only the document plan but also the scope of the
relationship. This process should include a detailed discussion of
the interactions between the two companies, project planning,
process expectations, and implementation of quality standards.
Interactions between the Two Companies
Interaction guidelines can be quite simple for freelances/sole
proprietors, but can be quite complex for FSPs, which may
benefit from the creation of a governance body consisting
Model
Freelance/ sole
proprietor
A single professional
medical writer contracting
with a Sponsor, usually
on a document-bydocument basis
Document scope is
basically unlimited within
the experience of the
individual writer
A CRO that is executing
a study provides the
supporting document
work for that study
Full service CRO
Can include protocols,
informed consent forms,
clinical study reports
(CSRs), investigator’s
brochures (IBs), even
regulatory filings
A medical writing
company (or department
within a CRO) that
dedicates a team of
medical writers to a
particular Sponsor
FSP
Usually involves extensive
training for a team
of writers in the Sponsor’s
processes and systems
Document scope is
usually very broad,
both study- and
programme-level
documents
Cost
Expertise/familiarity
Investment/convenience
Investment: can usually
contract on a documentby-document basis, can be
a lower upfront cost
commitment required
Varies: generally higher
than CRO or FSP for highly
experienced writers
Expertise varies: can often be
extremely high, must be
carefully vetted
Convenience: often very
straightforward to start
a contract.
Can be lower for less
experienced writers
Familiarity with a particular
Sponsor must be built over time
However, if a particular
freelance writer becomes
critical to a document plan,
the Sponsor must be careful
to schedule ahead – freelancers
only get paid when they are
writing, and will often have
multiple clients
Usually lower than freelance or
FSP on a document-bydocument basis
Can be bundled into study
costs, which can be a cost
advantage
Writers generally need to
maintain stricter budgets for
their writing time – as a result,
the initial cost may be lower,
but change controls orders can
increase costs
Costs are generally lower
than freelance, but higher
than full-service
CRO arrangements
Volume-based price discounts
are negotiable
Multiple costing models (time
and materials/hourly,
deliverable based)
are available
Investment: usually contracted
on a study-by-study or
programme-by-programme
basis, so forecasting work,
timelines and costs can be
straightforward
CROs tend to maintain broad
document expertise within their
organisations, but may have less
expertise in non-study related
document types
Familiarity with a sponsor is often
lower than other models, because
the writers are generally sourced
to multiple clients
Convenience: writers often
have strong internal
relationships with other
members of the study team,
when they are internal to the
CRO (statistics, clinical, medical
monitor, etc) – this can be a
huge advantage
Writers may be less flexible in
terms of working within
standard sponsor processes
and norms, usually less
‘customisation’ is available in the
document team approach
FSPs usually maintain
departments with broad and
deep expertise from both
a document type and therapeutic
area perspective
Familiarity with the Sponsor is a
key advantage of this model –
medical writers are dedicated
over time to the Sponsor and
establish familiarity and expertise
within their processes, systems
and norms
Investment: substantial. FSPs
generally expect a
commitment of a certain
threshold of document volume
and built-in fixed pricing
Convenience: lower for
individual documents or smaller
projects, due to the larger up
front investment
High for larger programmes,
due to the familiarity with the
Sponsor that builds over time
Table 1: Medical writing partnership models
of members from both companies. A formal escalation pathway
should be created for possible issues that may arise, with an
emphasis on keeping issues management as “local” as possible –
not every issue that might arise should require the involvement
of senior management. The establishment of Key Performance
Indicators (KPIs) for the relationship (even if they include no more
than the start and target end date for a single document) is an
important early step.
Project Planning
For one-off projects, planning is usually straightforward.
However, in cases where several documents are involved, project
planning requires close communication to ensure projects can
Functional service
providers (FSPs) represent an
area of innovation in medical
writing partnerships, creating
opportunities for efficiency
and optimisation across
larger document plans and
programmes
79
At the start of a partnership, the Sponsor and Service
Provider must establish which company’s standard operating
procedures for medical writing documents will be followed.
Beyond that, discussion and agreement on more detailed roles and
responsibilities are essential as well
be adequately staffed so that they are completed on time and
budget. For models where specific documents are not specified
at the contract stage, it is essential that a defined process of
forecasting and staffing documents is in place well before they
start; this “look-ahead” time should be agreed to by both parties
(3 months, 6 months, etc). Some documents, such as responses to
regulatory requests, may be difficult to forecast. However, there
should be a clearly defined mechanism on how these drop-in
requests will be communicated and how they will be resourced.
documents drafted by scientific experts within the Sponsor
company or drafted by the writer, who maintains the timeline,
etc. Some Sponsors may not include contract medical writers
in team meetings or critical strategic discussions. However, a
medical writer is best utilised when they are fully integrated into
the project team and truly understand the rationale behind the
document. Documenting these roles and responsibilities in a
shared guide or a Responsible/Accountable/Consulted/Informed
Matrix is a best practice.
For larger partnerships, a worthy goal is “strategic sourcing”:
the concept that the Service Provider knows the Sponsor’s
business well enough to make intelligent resourcing decisions
from a therapeutic area and document type perspective,
optimally matching the right writer to the right team. For this
to occur, the Sponsor needs to provide a transparent view
into their upcoming work and overall development priorities,
and the Service Provider needs to invest in the time to analyse
and intelligently staff against the plan/priorities. This is an
opportunity for the Service Provider to enhance the Sponsor’s
staffing plans, rather than simply meet a staffing need from a
capacity standpoint. Critical questions for project planning
and staff resourcing are presented in Table 2.
Implementation of Quality Standards
At the document level, an essential part of mapping out the
scope of a project is defining quality control (QC) measures
(QC review, formatting, copy-editing, etc) and planning their
implementation. It should be clear what guidelines are being
followed, which partner is providing these services, and at what
point during the process they will occur. For new relationships,
the Sponsor may want to consider providing additional quality
assurance checks, even if the Service Provider is performing the
bulk of the QC work, to ensure that expectations and standards
are equivalent across each company.
Process Expectations
At the start of a partnership, the Sponsor and Service Provider
must establish which company’s standard operating procedures
for medical writing documents will be followed. Beyond
that, discussion and agreement on more detailed roles and
responsibilities are essential as well. Who is responsible for
scheduling and running document kick-off meetings, are
At the partnership level, quality standards should be defined
as well. Communication about the relationship should be
happening at the project level (through lessons-learned
meetings), and also at the management/governance level.
Regular assessment of predefined KPIs should occur to
confirm that the relationship is functioning as intended, and
hopefully, is improving over time. Communication should be
occurring in both directions, not just the Sponsor evaluating
the Service Provider. The Sponsor should ensure that the
Project Forecasting
• Has the Sponsor mapped out the anticipated documents for each drug programme based on the current development phase?
• How will the Sponsor communicate the relative priority of projects, especially in cases where short-term resourcing conflicts arise?
• How will planned and ongoing projects be tracked and communicated between the Sponsor and the Service Provider?
• How far in advance should each project be resourced?
• How will ‘drop-in’ projects, eg, regulatory requests, be resourced?
• How will changes in anticipated timelines be communicated?
Staff Resourcing
• Are there sufficient resources to staff the forecasted project(s)?
• How will the Service Provider manage shorter-term peaks and valleys in workload?
• Does the assigned writer have experience in the relevant therapeutic area and document type? If not, will they be overseen by someone who does?
• Will the writer be trained on Sponsor-specific guidances, templates, etc by the Sponsor or the Service Provider (eg, the train-the-trainer model)?
• When do training activities need to occur so that the writer will be fully trained before the document starts?
• How will writer unavailability (sickness, paid time off, resignation, termination, etc) and changes to timelines be communicated and managed?
Table 2: Critical questions for project forecasting and staff resourcing
80
Metric
Definition
Types of documents
completed
Measure documents completed per type
(CSR, IB, briefing document, etc)
Calendar cycle times
Cycle times per draft, per review, per QC round –
how long are these activities taking?
Value
Allows for the calculation of documents completed per writer,
or per writer type (Junior Writer, Senior Writer, etc). Measurement
of writer productivity
Also allows for calculation of overall departmental productivity
and an understanding of the overall portfolio of work that
a department is producing
Allows for more accurate forecasting, and measures of
on-time delivery
Important for Service Providers to understand how to invoice,
calculate utilisation and realisation for budgetary purposes, support
resourcing estimates, and identify where potential efficiencies can
be gained
Document cycle
times
Timing of data locks
and TLF delivery
Time spent on
re-work
Number of drafts, overall hours per document
for writing and QC
Measure dates and number of re-locks and tables,
listing, figures (TLF) re-issues
These events are generally on the critical path for writing activities,
and disruption in these events – or the need to re-run data
programmes – is a common obstacle to on-time and on-budget
document work
Measure writing and QC time that is required to re-work
text or tables within a document, due to an error or
change in strategy
Re-work is problematic for the Sponsor, but can be crippling for the
Service Provider – particularly when writing resources are tight and
or pricing is deliverable-based
Often related to a failure of the quality checks within a particular
document. Should be categorised by document type to monitor
for trends
Number of major QC
findings or ‘unlocks’
Measure instances where updates are required after
document approvals; can include amendments, errata
Quality checklists
Pre-specified quality checklists that can be measured
for compliance
Satisfaction surveys
Important for Sponsors to understand the root causes of additional
drafts and overall time spent on writing and QC – is the Service
Provider creating drafts and finalising documents within a
reasonable timeframe? If not, is that because of issues with the
Service Provider or difficulties getting required information from
the Sponsor?
Surveys of writing team members of the quality and
experience of completing a particular document
Simply collecting the number of QC findings for a particular
document generally tends to be an overly granular measure and can
be difficult to correlate directly to the quality of the writing; may also
be QC reviewer dependent
Checklists/checkpoints can be put in place for individual drafts,
final documents, etc. In general, a quality measure of the
completeness of a document at a particular stage. May be less
useful as a KPI per se, but can be valuable to drive consistency
and compliance
Surveys are a subjective measure, but can be a useful assessment
of quality. Should be conducted in ‘both directions’ – the Sponsor
writing team members evaluating the quality of the writing, and
the Service Provider evaluating the experience working with
members within the Sponsor writing team
Surveys can also be conducted at the relationship level on a
quarterly or yearly basis to assess aspects like collaboration,
communication, etc
Budget
Planned versus actuals for both the Sponsor and
the Service Provider
Provides a measure of the financial health of the relationship
for both partners
It is recommended that the Sponsor and Service Provider agree
to a standard time for advanced notice before starting a document.
This KPI is a metric of how many of the documents completed within
a partnership met that standard advance notice
Planned versus
unplanned
documents
Record for each document when the assignment was
made, and when the document was started
Percent to forecast
What percentage of the documents completed
matched the initial forecast of the projected work for
a quarter or a year?
Assesses the Sponsor’s accuracy in forecasting work as well as the
Service Provider’s ability to deliver to plan. Even if the forecast of
the overall document ‘volume’ is accurate, are the documents
that are projected to start the same documents that are being
completed? Is there a high degree of drop-out and/or replacement?
Turnover and
resource
changes
Measure of the instances where the Service Provider
either had a writer leave the partnership, or had to
replace/reassign a projected writer due to an
assignment conflict
For FSP relationships that depend on a dedicated set of writers,
this can be an important measure of the return on a training
investment from the Sponsor perspective. It can also serve as a
measure of the general health of the relationship – if the Service
Provider is losing a high number of staff, is it related to the working
conditions within the partnership?
In some larger relationships, the percentage of ‘drop-in’ work can be
as high as 30-50% – this has a significant effect on the capacity of a
Service Provider to conduct thoughtful resourcing on a project-by
project basis
Table 3: KPIs for a medical writing partnership
81
KPIs should be measured ‘in both directions’ – for a
successful partnership, it is important not only for the sponsor to
evaluate the performance of the service provider, but also for the
sponsor to assess its own performance in meeting the needs and
expectations of the service provider
clarity of expectations, the work environment for the writers,
and the financial health of the relationship are working
successfully for the Service Provider as well.
Key Performance Indicators
Pharmaceutical document work has been particularly difficult to
quantitatively assess, as more traditional editing standards (words
per page, pages per document, number of typesetting errors,
etc) are poor quantitative stand-ins for the important qualitative
measures of a regulatory document:
• Was the document written in a manner that was fit for purpose?
•D
id it meet regulatory standards?
•D
id it appropriately advance the development programme on
time and on budget?
However, it is important to continue to develop and implement
quantitative measures of medical writing because measuring
performance is the key first step in understanding and
improving performance.
Within a Sponsor-Service Provider partnership, it is
recommended that KPIs be agreed to at the beginning of
the relationship, and that they be monitored, discussed, and
evaluated on an ongoing basis. KPIs for medical writing can be
categorised at the document, departmental, and relationship
level, ranging from simple measurements of dates and cycle
times to more advanced measures of document quality.
Examples of proposed KPIs for a medical writing partnership
are provided in Table 3.
It is recommended that KPIs be measured “in both directions”
– for a successful partnership, it is important not only for the
Sponsor to evaluate the performance of the Service Provider, but
for the Sponsor to also evaluate its own performance in meeting
the needs and expectations of the Service Provider. Furthermore,
it is recommended that KPIs be transparently reviewed by a
governance team of the Sponsor and the Service Provider
together, working from the same shared data set. Ensuring that
each partner is working with the same set of facts is critical to
working openly on challenges and making informed decisions
with respect to process improvement or innovation efforts.
The reliable collection of a set of KPIs gives medical writing
managers the ability to assess and improve performance and
82
affords Service Providers the opportunity to ensure their
own financial solvency and quantify the value of
their contributions. Furthermore, it empowers both
to effectively communicate the critical contribution of
medical writing partnerships to the development
of new medications.
Conclusion
Successful medical writing partnerships are based on
great medical writing talent, proactive planning, and
mutual respect for the value that each partner can
provide. Matching the right Service Provider with the right
document plan is a key first step, but no matter what the
model, setting clear expectations for the partnership is
critical. In the current global development environment,
establishing strong and lasting working relationships
with thoughtful investment in cooperative success is
a competitive advantage for both Sponsors and
Service Providers.
About the authors
Michael John Mihm is currently Director
of Medical Writing at Astellas Pharma.
He has been involved in drug development
for over 20 years in both the pharma and
service industries, as well as in academia,
and has authored over 100 publications in
the areas of diabetes and cardiovascular
medicine. Michael has a doctorate in Pharmacology from
The Ohio State University, US.
Email: [email protected]
Cortney Chertova is a Senior Document
Manager at Randstad Life Sciences, where
she manages a team of writers in an FSP
model. She is an accomplished medical
writer with experience in global clinical
and regulatory documents across various
therapeutic areas, particularly oncology.
Cortney holds a PhD in Biochemistry from the University
of Washington, US.
Email: [email protected] ICT
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